Synthesis method of pholcodine monohydrate

Abstract

The present invention provides a pholcodine monohydrate synthesis method, and relates to the technical field of chemical combination drug synthesis, commercially available N-(2-chloroethyl) morpholine hydrochloride and morphine base are subjected to a reaction under the alkaline action of potassium carbonate by using acetone as a solvent to obtain a pholcodine target product with high yield. And recrystallizing the crude product in deionized water to obtain a pholcodine monohydrate crystal. Through the combined action of the screening alkali and the solvent, the use of strong alkali such as sodium hydroxide is avoided, and the reaction safety is improved; in addition, through recrystallization of the product in water, not only is the pholcodine monohydrate successfully synthesized, but also the effect of further purifying the compound is achieved.

Description

Technical Field

[0001] This invention relates to the field of chemical drug synthesis technology, specifically a method for synthesizing pholcodine monohydrate. Background Technology

[0002] Pholcodine, chemically named 17-methyl-3-[2-(4-morpholinyl)ethoxy]-4,5α-epoxy-7,8-disehydromorphinan-6α-ol, is an organic compound, also known as pholcodine or morpholinomorphine, and is a semi-synthetic derivative of morphine. Pharmacologically, pholcodine acts similarly to dextromethorphan and also has antitussive and analgesic effects similar to codeine. Its oral efficacy is better than codeine, especially for dry cough. It is less toxic and addictive than codeine; its respiratory depression is weaker than morphine; and it is well-tolerated in newborns and children, without causing constipation or digestive disorders. The structural formula of pholcodine is as follows:

[0003] The currently reported synthetic routes for pholcodine are as follows: (1): Morpholine is synthesized into morpholine ethanol, which is then chlorinated to form N-(2-chloroethyl)morpholine hydrochloride, which is then substituted with morphine to obtain pholcodine (Annales Pharmaceutiques Francaises, 1950, vol. 8, p. 261; Arzneimittel-Forschung / Drug Research, 1958, vol. 8, p. 325). (2): The intermediate obtained by reacting 2-chloroethylbenzenesulfonate with morphine is then reacted with morpholine to obtain pholcodine. (3): The method developed by Humanwell Healthcare Group first introduces an electrophilic haloalkane substituent onto morphine, and then uses nano-CuI to activate the haloalkane to catalyze its reaction with morpholine to obtain pholcodine.

[0004] The above routes involve lengthy steps and risks such as the use of toxic reagents (e.g., 2-chloroethylbenzenesulfonate needs to be prepared from highly toxic chloroethanol; the use of organometallic reagents poses a risk of metal residue), and there is no specific synthetic method for pholcodine monohydrate. Summary of the Invention

[0005] This invention provides a method for synthesizing pholcodine monohydrate, which solves at least one of the technical problems mentioned in the background art.

[0006] To solve the above-mentioned technical problems, this invention discloses a method for synthesizing pholcodine monohydrate, comprising: Step 1: At room temperature, morphine base was dissolved in acetone and nitrogen was introduced; then potassium carbonate and N-(2-chloroethyl)morpholine hydrochloride were added under a nitrogen atmosphere, and the mixture was refluxed overnight; after the reaction was completed, deionized water was added to quench the reaction, the layers were separated, extracted with ethyl acetate several times, washed with saturated brine, dried with anhydrous sodium sulfate, and then the reaction solution was concentrated and column chromatography was used to obtain free pholcodine base; Step 2: Place the free base of pholcodine in a reaction flask, then add deionized water. Attach a reflux condenser to the reaction flask and heat it under reflux until the solid dissolves. After the reaction solution in the flask returns to room temperature, transfer the flask to a refrigerator for crystallization. After overnight, remove the flask from the refrigerator and allow it to crystallize at room temperature. Once crystallization is complete and no new solid particles are formed, filter to obtain pholcodine monohydrate.

[0007] Preferably, the reaction formula in step 1 is: .

[0008] Preferably, the reaction formula in step 2 is:

[0009] Preferably, the reaction flask is a single-necked flask.

[0010] Preferably, in step 1, the mixture is refluxed and stirred overnight at 60°C to 80°C.

[0011] Preferably, in step 2, after the reflux condenser is installed, the mixture is refluxed and stirred in an oil bath.

[0012] Preferably, the temperature of the oil bath is 110℃~120℃.

[0013] Preferably, the crystallization time at room temperature is greater than 3 days.

[0014] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The technical solution of this application involves reacting commercially available N-(2-chloroethyl)morpholine hydrochloride with morphine base in the presence of potassium carbonate and acetone as a solvent to obtain the target product, pholcodine, in high yield. Subsequently, pholcodine monohydrate crystals are obtained by recrystallizing the crude product in deionized water. This invention improves the safety of the reaction by selecting appropriate combinations of base and solvent, avoiding the use of strong bases such as sodium hydroxide. Furthermore, the recrystallization of the product in water not only successfully synthesizes pholcodine monohydrate but also further purifies the compound.

[0016] Advantages over publicly available synthetic methods: (1): The safety and mildness of the reaction are improved by avoiding the use of dangerous strong bases.

[0017] (2): The reaction is direct and simple, avoiding the use of metal reagents that are easy to leave residues, and has good operability.

[0018] (3): An efficient method for synthesizing pholcodine monohydrate was found, which also plays a role in purification.

[0019] Compared with existing technologies, this method avoids the use of hazardous strong alkalis, thus simplifying the post-processing procedure; it avoids the use of toxic and metallic reagents, thus avoiding the problem of metal or toxic reagent residues; and through the recrystallization process, it achieves two goals at once: it not only purifies the product but also provides an efficient method for synthesizing pholcodine monohydrate. Attached Figure Description

[0020] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings: Figure 1 This is a schematic diagram of the process of the present invention; Figure 2 The 1H NMR spectrum of pholcodin monohydrate prepared according to an embodiment of the present invention; Figure 3 Carbon NMR spectrum of pholcodin monohydrate prepared according to an embodiment of the present invention; Figure 4 The TGA test results of pholcodine monohydrate prepared according to an embodiment of the present invention are shown in the figure. Figure 5 The HPLC test results of pholcodine monohydrate prepared according to the embodiments of the present invention are shown in the figure. Figure 6 Infrared spectroscopy results of pholcodine monohydrate prepared according to an embodiment of the present invention; Figure 7 The high-resolution mass spectrometry result of the pholcodine monohydrate prepared according to an embodiment of the present invention is shown. Detailed Implementation

[0021] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0022] Furthermore, in this invention, the use of terms such as "first" and "second" is for descriptive purposes only and does not specifically refer to any order or sequence, nor is it intended to limit the invention. They are merely used to distinguish components or operations described using the same technical terms and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined with "first" or "second" may explicitly or implicitly include at least one of those features. Additionally, the technical solutions and features of the various embodiments can be combined with each other, but this must be based on the ability of those skilled in the art to implement them. If a combination of technical solutions is contradictory or impossible to implement, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection claimed by this invention.

[0023] In this invention, in step 1, the mass ratio of the raw material morphine to potassium carbonate is 1:1.3 to 1:5; The mass ratio of raw material morphine to N-(2-chloroethyl)morpholine hydrochloride is 1:1.3 to 1:5.

[0024] In step 2, the mass ratio of morphine to deionized water is 1:20 to 1:30.

[0025] The present invention provides the following specific embodiments: See the attached diagram in the instruction manual. Figures 1-7 This embodiment relates to a method for preparing high-purity pholcodine monohydrate, the target product being pholcodine monohydrate, and its synthetic route is as follows:

[0026] Step 1: Synthesis of Intermediate I: Add 10.0 g (35.09 mmol) of morphine and 500 mL of acetone to a 1 L dry round-bottom flask, then attach a reflux condenser and purge with nitrogen three times. Next, slowly add 14.5 g (105.26 mmol) of potassium carbonate and 19.6 g (105.26 mmol) of N-(2-chloroethyl)morpholine hydrochloride. After the additions are complete, allow the reaction to proceed at 60 °C. o The mixture was refluxed and stirred overnight at C. After the reaction was complete, deionized water (100 mL) was added to quench the reaction. After separation, the mixture was extracted three times with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then concentrated by column chromatography (dichloromethane:methanol = 10:1) to give pholcodine free base (10.2 g, yield 73%) as a hygroscopic pale yellow solid.

[0027] Step 2: Synthesis of pholcodine monohydrate: Add 1.5 g of free pholcodine base to a 100 mL dry single-necked flask, followed by 30 mL of deionized water. Attach a reflux condenser and incubate at 110°C. o The reaction mixture was refluxed in an oil bath with stirring, and the dissolution status was observed while stirring. A small amount of deionized water was added during this period to ensure complete dissolution of the pholcodine solid. The reaction solution was then brought to room temperature and transferred to a refrigerator for crystallization overnight. The next day, the reaction flask was removed from the refrigerator and allowed to crystallize slowly at room temperature for approximately 3–4 days. Once crystallization was complete and no new solid particles were formed, the mixture was filtered to obtain pholcodine monohydrate (396 mg, yield 25%), which was a white crystalline powder. The two-step yield was 18%, HPLC purity >99.838%, single impurity content <0.135%, and total impurity content <0.162%, as shown in the table below:

[0028] The 1H NMR spectrum of pholcodine monohydrate is shown below. Figure 2 : 1 H NMR (600 MHz, CDCl3) δ 6.65-6.64 (m,1H), 6.53-6.52 (m, 1H), 5.68-5.65 (m, 1H), 5.28-5.25 (m, 1H), 4.87-4.86 (m,1H), 4.26-4.22 (m, 1H), 4.17-4.14 (m, 1H), 4.12-4.08 (m, 1H), 3.73-3.71 (m,4H), 3.35-3.34 (m, 1H), 3.04-3.01 (m, 1H), 2.74-2.72 (m, 2H), 2.68-2.66 (m,1H), 2.60-2.51 (m, 5H), 2.43 (s, 3H), 2.42-2.37 (m, 1H), 2.31-2.27 (m, 1H), 2.09-2.04 (m, 1H), 1.87-1.84 (m, 1H).

[0029] The 1H NMR spectrum of pholcodine monohydrate is shown below. Figure 3 : 13 H NMR (151 MHz, CDCl3) δ 147.0, 141.1,133.6, 131.5, 128.4, 127.9, 119.8, 115.7, 91.5, 67.3, 66.9, 66.6, 59.0, 57.9,54.2, 46.6, 43.2, 43.0, 40.8, 35.8, 20.6.

[0030] Figure 7In the middle, the theory [M+H] + m / z 399.22783; Measured [M+H] + m / z 399.22817.

[0031] The beneficial effects of the above technical solution are as follows: The technical solution of this application involves reacting commercially available N-(2-chloroethyl)morpholine hydrochloride with morphine base in the presence of potassium carbonate and acetone as a solvent to obtain the target product, pholcodine, in high yield. Subsequently, pholcodine monohydrate crystals are obtained by recrystallizing the crude product in deionized water. This invention improves the safety of the reaction by selecting appropriate combinations of base and solvent, avoiding the use of strong bases such as sodium hydroxide. Furthermore, the recrystallization of the product in water not only successfully synthesizes pholcodine monohydrate but also further purifies the compound.

[0032] Advantages over publicly available synthetic methods: (1): The safety and mildness of the reaction are improved by avoiding the use of dangerous strong bases.

[0033] (2): The reaction is direct and simple, avoiding the use of metal reagents that are easy to leave residues, and has good operability.

[0034] (3): An efficient method for synthesizing pholcodine monohydrate was found, which also plays a role in purification.

[0035] Compared with existing technologies, this method avoids the use of hazardous strong alkalis, thus simplifying the post-processing procedure; it avoids the use of toxic and metallic reagents, thus avoiding the problem of metal or toxic reagent residues; and through the recrystallization process, it achieves two goals at once: it not only purifies the product but also provides an efficient method for synthesizing pholcodine monohydrate.

[0036] In one embodiment, the target process is divided into multiple stages, including a room temperature dissolution stage, a nitrogen purging buffer stage, a feeding stage, and a reflux overnight stage. The target process is described as follows: "At room temperature, morphine is dissolved in acetone solvent and nitrogen is purged; then potassium carbonate and N-(2-chloroethyl)morpholine hydrochloride are added under a nitrogen atmosphere, and the mixture is refluxed overnight after the addition is complete." The pre-determined processes before the batch start of the target process include: Step 01: At room temperature, dissolve the batch of morphine alkaloid sample to be used in the batch of acetone solvent sample to be used, and determine the actual solubility; Step 02: Obtain the theoretical morphine concentration of the batch of morphine to be used in the batch of acetone to be used. Based on the actual solubility and the theoretical morphine concentration of the batch of morphine to be used in the batch of acetone to be used, determine the dissolution deviation coefficient. Based on the dissolution deviation coefficient, correct or issue an alarm for the theoretical morphine concentration of the batch of morphine to be used in the batch of acetone to be used. Dissolution deviation coefficient = (theoretical morphine concentration of the batch of morphine to be used in acetone to be used - actual solubility) ÷ theoretical morphine concentration of the batch of morphine to be used in acetone to be used; When the dissolution deviation coefficient is less than or equal to 0.05, then: The corrected morphine concentration of the batch of morphine to be used in acetone is equal to the theoretical morphine concentration of the batch of morphine to be used in acetone. An alarm will be triggered if the dissolution deviation coefficient is greater than 0.2. When the dissolution deviation coefficient is greater than 0.05 and less than or equal to 0.2, then: The corrected morphine concentration of the batch of morphine to be used in acetone is equal to H times the theoretical morphine concentration of the batch of morphine to be used in acetone. The value of H is between 0.92 and 0.98 times (determined by "matching the deviation between theoretical concentration and actual solubility + verification by experimental data"; the larger the deviation, the smaller the value). Step 03: Obtain the standard nitrogen flow rate of pure acetone at room temperature under the current conditions of the target process (reaction conditions, including reaction vessel conditions); and obtain the vapor pressure of pure acetone at the current room temperature. The standard nitrogen flow rate for the room temperature dissolution section of pure acetone under the current conditions of the target process (reaction conditions, including reaction vessel conditions and temperature conditions) is determined through preliminary experiments under the "target reaction conditions (including reaction vessel conditions)" and selected as "the lowest nitrogen flow rate that can maintain the inert atmosphere of the dissolution system (to avoid oxidation of acetone / morphine), suppress the loss of acetone due to volatilization during the dissolution process, and not interfere with the dissolution rate of morphine". The vapor pressure of pure acetone at the current room temperature: Based on the current room temperature, refer to the "Acetone Vapor Pressure-Temperature Reference Table" to obtain the theoretical vapor pressure of pure acetone at this temperature (for example, at 25℃, the vapor pressure of acetone is approximately 30.9 kPa). The vapor pressure of acetone is an inherent physical property. The scientific research field has conducted a large number of experiments to determine the vapor pressure data at different temperatures (such as key temperature points such as 20℃, 25℃, and 30℃). Combined with the Clausius-Clapeyron equation (which describes the relationship between vapor pressure and temperature), vapor pressure curves for common room temperature ranges are fitted, and then theoretical values ​​corresponding to different room temperatures are obtained.

[0037] Step 04: Determine the pressure coefficient based on the vapor pressure of pure acetone at the current room temperature and the vapor pressure of pure acetone at standard room temperature (e.g., 25°C). Determine the required nitrogen flow rate for the room temperature sample dissolution stage based on the corrected morphine concentration of the batch of morphine to be used dissolved in the batch of acetone to be used, the pressure coefficient, and the standard nitrogen flow rate of the room temperature dissolution section when using pure acetone. Pressure coefficient m = vapor pressure of pure acetone at current room temperature ÷ vapor pressure of pure acetone at standard room temperature; ; in, A nitrogen flow rate needs to be set for the room temperature sample dissolution stage; The corrected morphine concentration (in mmol / L) is the concentration of morphine in the batch to be used in acetone. This is the concentration-flow rate adjustment coefficient (with a value of 0.03 to 0.12). The standard nitrogen flow rate for the room temperature dissolution section of pure acetone; The unit is morphine base concentration (1 mmol / L); m ranges from 0.8 to 1.2; The correction factor for the effect of morphine concentration on nitrogen flow rate was determined through preliminary experiments: In a fixed container at room temperature, the appropriate nitrogen flow rate (which maintains an inert atmosphere in the dissolution system, inhibits volatilization, and does not interfere with the morphine dissolution rate) was tested at different concentrations (5 / 10 / 20 mmol / L). This correction factor was used to evaluate the relationship between the flow rate increment and the relative value of the concentration. "Perform linear regression, and the slope is k (with a value of 0.03 to 0.12, and a smaller value for low concentrations);" Step 05: Determine the required nitrogen flow rate for the buffer section after nitrogen replacement, the feeding stage, and the overnight reflux stage based on the required nitrogen flow rate during the room temperature sample dissolution stage. When executing the target process based on the batches of morphine base and acetone solvent to be used, control the nitrogen purging of the reaction vessel at each stage based on the required nitrogen flow rate for each stage (the actual nitrogen flow rate is the corresponding required nitrogen flow rate); The required nitrogen flow rate for the buffer section after nitrogen replacement is 0.62 to 0.73 times (preferably 0.68 times). The required nitrogen flow rate for the room temperature sample dissolution stage is as follows: The required nitrogen flow rate during the feeding stage is 1.25 to 1.5 times (preferably 1.32 times). The required nitrogen flow rate during the room temperature sample dissolution stage is as follows: The required nitrogen flow rate for the overnight reflux stage is 0.62 to 0.71 times (preferably 0.66 times) the required nitrogen flow rate for the room temperature sample dissolution stage; If the reaction flask volume is 500 mL Take a flow rate of 0.5–0.8 L / min (preferably 0.65 L / min); if the reaction flask volume is 1000 mL, Use a flow rate of 1.0 to 1.5 L / min (preferably 1.25 L / min).

[0038] First, select a batch of "high-quality morphine and high-quality acetone (fixed concentration) that meet the standards in terms of performance, activity, and quality" - based on this set of high-quality raw materials, the actual concentration of the solution according to the predetermined dissolution ratio (determined according to the reaction requirements) is the theoretical concentration benchmark for subsequent batch experiments.

[0039] The theoretical morphine concentration of the batch of morphine to be used in acetone is the theoretical concentration benchmark corresponding to the dissolution ratio and acetone concentration and purity of the batch to be used. The beneficial effects of the above technical solution are as follows: By employing "pre-screening of high-quality raw materials + calibration of actual solubility," the hidden risk of "dissolution failure due to fluctuations in raw material activity" in batch experiments is completely avoided. Furthermore, the precise matching of corrected concentrations and actual solubility reduces material ratio errors in subsequent reactions, providing a foundation for consistent purity in batch products.

[0040] By combining the pressure coefficient, the dynamic increase in flow rate can reduce acetone evaporation loss; and the introduction of the concentration-flow coefficient k allows the nitrogen consumption during low-concentration dissolution to be "precisely reduced" according to demand, resulting in a reduction in overall nitrogen consumption compared to traditional processes. This "on-demand" flow control not only avoids oxidation side reactions caused by insufficient inert atmosphere but also reduces auxiliary material costs.

[0041] When the deviation is greater than 0.2, raw materials with substandard solubility are intercepted in advance, avoiding material waste caused by "dissolution failure only being discovered after batch production" in traditional processes. The proportional design of the flow rate at each stage allows new operators to quickly reproduce a stable process without relying on "experience or feel".

[0042] In one embodiment, before the heating reflux in step 2, the following is also included: Step 001: Obtain the viscosity of the aqueous solution (the solution obtained by dissolving pholcodine free base in deionized water) corresponding to the current concentration of pholcodine free base at the reflux temperature in Step 2, and determine the viscosity factor based on the viscosity of the standard pholcodine aqueous solution; Viscosity factor = viscosity of aqueous solution corresponding to the current free base concentration of pholcodine at the reflux temperature in step 2 ÷ viscosity of standard pholcodine aqueous solution; The higher the viscosity factor, the greater the resistance to molecular diffusion during dissolution; Viscosity of standard pholcodine aqueous solution: The viscosity reference value is obtained by pre-experimental determination of the aqueous solution formed by dissolving pholcodine free base in deionized water under the conditions of fixed reflux temperature + standard concentration (determined based on the actual commonly used ratio in step 2. A typical ratio corresponding to the concentration can be selected as the general standard concentration, or a specific standard concentration corresponding to each range can be set for different ratio ranges) . Current free base concentration of pholcodine: refers to the actual concentration (unit: mmol / L) of the solution formed after the batch of free base of pholcodine to be used is dissolved in deionized water at the reflux temperature (e.g., 100°C) during the heating and reflux in step 2. Step 002: Obtain the vapor pressure of deionized water at the reflux temperature in Step 2, and determine the vapor pressure ratio; Gas pressure ratio = Deionized water vapor pressure at reflux temperature ÷ Liquid vapor pressure of the aqueous solution of pholcodine at initial room temperature; The liquid vapor pressure of pholcodine aqueous solution at initial room temperature: "The liquid vapor pressure when free pholcodine base is mixed with deionized water, stirred until completely dissolved, and allowed to stand at initial room temperature (e.g., 25°C)"; The pressure ratio directly reflects the change in the evaporation capacity of the solvent (deionized water) in the system during the process of "standing at room temperature → heating and reflux" - the larger the ratio, the stronger the driving force for boiling / evaporation of the solvent during reflux. Step 003: Determine the actual heat transfer resistance coefficient by combining the viscosity factor and the air pressure ratio, and determine the target oil bath temperature based on the actual heat transfer resistance coefficient.

[0043] The actual heat transfer resistance coefficient is determined based on the viscosity factor and air pressure ratio; Actual heat transfer resistance coefficient = actual viscosity factor ÷ actual air pressure ratio; Actual heat transfer resistance coefficient > 1.1 (high solution viscosity and small water vapor pressure difference during reflux, resulting in high heat transfer resistance): Target heating temperature = reference heating temperature × 1.05; Reference heating temperature: refers to the oil bath set temperature (reference heating temperature) that can maintain stable reflux under the "target reflux temperature (e.g., 100℃) and standard concentration". For example, the preliminary experimental determination is 110~120℃ (the reference heating temperature is allowed to have a certain fluctuation range, such as ±0.5℃). 0.85≤Actual heat transfer resistance coefficient≤1.1 (matching heat transfer with boiling demand): Target heating temperature = Reference heating temperature; Actual heat transfer resistance coefficient < 0.85 (low solution viscosity and large water vapor pressure difference during reflux, resulting in rapid heat transfer): Target heating temperature = reference heating temperature × 0.98; The smaller the heat transfer resistance coefficient, the lower the solution viscosity and the greater the vapor pressure difference, resulting in faster heat transfer. This means that the reflux temperature can be controlled by only slightly reducing the oil bath temperature (without the need for significant cooling). The allowable range for the heat transfer resistance coefficient is 0.6 to 1.4; Step 004: Determine the staged preheating strategy based on the heat transfer resistance coefficient; Actual heat transfer resistance coefficient > 1.1: The oil bath is first heated to the first temperature, and the solution is stirred at the first stirring rate for 4 minutes while maintaining this temperature; after preheating, the oil bath is heated to the target heating temperature at the first rate. The first temperature is "95℃-10℃×(actual heat transfer resistance coefficient-1.1)" rounded down; The first stirring rate is as follows: for solution volume ≤ 200 mL: 150~160 r / min; for 200 mL < volume ≤ 500 mL: 130~140 r / min; for volume > 500 mL: 110~120 r / min. The first rate is: volume ≤ 200mL: 15~17℃ / min; 200mL < volume ≤ 500mL: 13~15℃ / min; volume > 500mL: 11~13℃ / min; 0.85≤actual heat transfer resistance coefficient≤1.1: The oil bath is directly heated to the second temperature, held for 2 minutes, and then heated to the target heating temperature at the second rate; The second temperature is "100℃ + 5℃ × (actual heat transfer resistance coefficient - 0.85)" rounded down; The second rate is as follows: volume ≤ 200 mL: 12~14℃ / min; 200 mL < volume ≤ 500 mL: 10~12℃ / min; volume > 500 mL: 8~10℃ / min; Actual heat transfer resistance coefficient < 0.85: The oil bath is heated to the third temperature at a rate of "10℃ / min + 2℃ / min × (0.85 - actual heat transfer resistance coefficient)" while maintaining the third stirring rate during the process; after preheating, the oil bath is heated to the target heating temperature at the third rate. The third temperature is "105℃-5℃×(0.85-actual heat transfer resistance coefficient)" rounded down; Third stirring rate: Volume ≤ 200 mL: 80~90 r / min; 200 mL < Volume ≤ 500 mL: 70~80 r / min; Volume > 500 mL: 60~70 r / min; Third rate: Volume ≤ 200 mL: 8~10℃ / min; 200 mL < Volume ≤ 500 mL: 7~9℃ / min; Volume > 500 mL: 6~8℃ / min; The rounding rule is to round to the nearest integer temperature. When performing step 2 based on the raw materials to be used, the oil bath is controlled based on the target oil bath temperature and the staged preheating strategy. The beneficial effects of the above technical solution are as follows: In traditional processes, oil bath temperatures are often fixed based on experience, which can easily lead to problems such as insufficient heat transfer (slow dissolution) in high-viscosity solutions or overheating (excessive solvent evaporation) in low-viscosity solutions. This solution achieves dynamic and precise adaptation between oil bath temperature and solution state through a quantitative link of "viscosity factor → air pressure ratio → heat transfer resistance coefficient". Heat transfer resistance coefficient > 1.1: The oil bath temperature is finely adjusted to 1.05 times the reference heating temperature, which not only makes up for the heat transfer resistance, but also avoids the reflux temperature from being too high due to excessive temperature, and improves the matching degree between the actual viscosity of the solution and the heat input. Heat transfer resistance coefficient <0.85: The oil bath temperature is finely adjusted to 0.98 times the reference heating temperature. While controlling the heat transfer rate, the reflux temperature is kept stable at around the corresponding target temperature, and the matching degree between heat input and boiling requirements is improved.

[0044] In high-viscosity scenarios, "medium-temperature stirring and preheating" utilizes the weakening effect of temperature on viscosity to reduce the initial viscosity of the solution, decrease the diffusion resistance of solid particles, and increase the dissolution rate in the subsequent reflux stage. Staged preheating ensures that the solution reaches near the boiling threshold before formal reflux, shortening the time to "heat to stable reflux" and reducing the total process time.

[0045] The design of matching the oil bath heating rate and stirring rate, combined with small temperature adjustments, controls the fluctuation range of solution temperature within a suitable range during reflux. The stable reflux temperature controls the evaporation rate of the solvent (deionized water) to 0.5–0.8 mL / h, which is lower than that of traditional processes, avoiding uneven product concentration caused by excessive solvent loss; the batch-to-batch solid dissolution time deviation is reduced, and the crystal form of the product (pholcodin monohydrate) is uniformly improved. This solution supports setting specific standard concentrations for different pholcodin ratio ranges.

[0046] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing pholcodin monohydrate, characterized in that: include: Step 1: At room temperature, dissolve morphine in acetone and replace the nitrogen gas. Potassium carbonate and N-(2-chloroethyl)morpholine hydrochloride were then added under a nitrogen atmosphere, and the mixture was refluxed overnight. After the reaction was completed, deionized water was added to quench the reaction, and the mixture was extracted with ethyl acetate multiple times after separation. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and then the reaction solution was concentrated and column chromatography was used to obtain free pholcodine base. Step 2: Place the free base of pholcodine in a reaction flask, then add deionized water. Attach a reflux condenser to the reaction flask and heat it under reflux until the solid dissolves. After the reaction solution in the flask returns to room temperature, transfer the flask to a refrigerator for crystallization. After overnight crystallization, remove the flask from the refrigerator and allow it to crystallize at room temperature. After crystallization is complete and no new solid particles are formed, the mixture is filtered to obtain pholcodine monohydrate.

2. The method for synthesizing pholcodin monohydrate according to claim 1, characterized in that: The reaction formula for step 1 is: 。 3. The method for synthesizing pholcodin monohydrate according to claim 2, characterized in that: The reaction formula for step 2 is: 。 4. The method for synthesizing pholcodin monohydrate according to claim 1, characterized in that: The reaction flask is a single-necked flask.

5. The method for synthesizing pholcodin monohydrate according to claim 1, characterized in that: In step 1, the mixture is refluxed and stirred overnight at 60℃~80℃.

6. The method for synthesizing pholcodin monohydrate according to claim 1, characterized in that: After installing the reflux condenser in step 2, the mixture is refluxed and stirred in an oil bath.

7. The method for synthesizing pholcodin monohydrate according to claim 6, characterized in that: The temperature of the oil bath is 110℃~120℃.

8. The method for synthesizing pholcodin monohydrate according to claim 1, characterized in that: Crystallization time at room temperature is greater than 3 days.

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