A sodium falafenamide hydrochloride intermediate and its preparation method

Abstract

This application discloses a method for preparing a nalfarafen hydrochloride intermediate, comprising: repeatedly adding N-methylbenzylamine and anhydrous formic acid of Formula II to naltrexone of Formula I to carry out a reductive amination reaction to generate a nalfarafen hydrochloride intermediate containing Formula III. The synthetic route is as follows: it significantly improves the reaction conversion rate of the raw material naltrexone and the effective conversion rate to the target product nalfarafen hydrochloride intermediate of Formula III.

Description

Technical Field

[0001] This application belongs to the field of drug synthesis technology, specifically relating to a method for preparing a nalfarafen hydrochloride intermediate. Background Technology

[0002] Nafaprafen Hydrochloride It is a highly selective κ(kappa)-opioid receptor agonist developed by Toray in Japan. It is mainly used to treat uremic pruritus associated with hemodialysis, especially when existing therapies or treatments are ineffective. It has shown good efficacy and safety in improving patients' quality of life.

[0003] Currently, there are many reported synthetic routes for nalfapramine hydrochloride-like compounds. Among them, the "Improved Synthetic Process of Nafurafen Hydrochloride," published in the Chinese Journal of Medicinal Chemistry in April 2024 by Lunan Pharmaceutical Group Co., Ltd., Shandong New Era Pharmaceutical Co., Ltd., and the National Engineering Research Center for Chiral Pharmaceuticals, uses naltrexone hydrochloride as the starting material. After salting, it first undergoes a reductive amination reaction with N-methylbenzylamine to generate nalfapramine hydrochloride intermediate of formula III. This intermediate of formula III nalfapramine hydrochloride is then catalytically hydrogenated to remove the benzyl group, yielding formula VI, namely 6β-N-methyl-naltrexamine. Formula VI reacts with formula V ((E)-3-(furan-3-yl)acryloyl chloride) under specific conditions to generate nalfapramine hydrochloride. The synthetic route of nalfapramine hydrochloride is as follows:

[0004]

[0005] The technical route for preparing the nalfarafen hydrochloride intermediate shown in Formula III involves the following steps: naltrexone hydrochloride is desalted to generate naltrexone, which then undergoes a reductive amination reaction with N-methylbenzylamine. While this process achieves a high conversion rate of the active pharmaceutical ingredient naltrexone, the use of sodium cyanoborohydride as a hydrogen donor results in the formation of highly toxic cyanide, posing a significant hazard. Furthermore, the reduction process generates numerous impurities, leading to a very low effective conversion rate to the target product, the nalfarafen hydrochloride intermediate shown in Formula III. Additionally, wastewater treatment is difficult, hindering industrial-scale production. As a crucial intermediate in the synthesis of nalfarafen hydrochloride, the yield and purity of the intermediate directly impact the quality and market supply of the drug. Therefore, finding a safe and environmentally friendly method that, while maintaining a high conversion rate of naltrexone, also improves the effective conversion rate of naltrexone to the target product, the nalfarafen hydrochloride intermediate shown in Formula III, remains a problem that needs to be solved by those skilled in the art. Summary of the Invention

[0006] To address the aforementioned issues, this application provides a method for preparing nalfarafen hydrochloride intermediates, which significantly improves the reaction conversion rate of the raw material naltrexone and the effective conversion rate into the target product nalfarafen hydrochloride intermediate shown in Formula III.

[0007] The present invention provides a method for preparing a nalfarafen hydrochloride intermediate, comprising the following steps:

[0008] A reductive amination reaction was carried out by repeatedly adding N-methylbenzylamine (Formula II) and anhydrous formic acid to naltrexone (Formula I) to generate a nalfarafen hydrochloride intermediate containing Formula III.

[0009] The synthesis route is as follows:

[0010]

[0011] This invention uses anhydrous formic acid as a hydrogen donor. The anhydrous formic acid decomposes into hydrogen and carbon dioxide under high-temperature conditions, avoiding the generation of highly toxic cyanide. Furthermore, the reductive amination reaction is reversible. During the reaction, atmospheric distillation is required to remove the water produced, and N-methylbenzylamine and anhydrous formic acid are added repeatedly. This improves the conversion rate of the raw material naltrexone and the effective conversion rate to the nalfarafen hydrochloride intermediate shown in Formula III.

[0012] In one embodiment of the present invention, based on the molar amount of naltrexone, the initial amount of N-methylbenzylamine is ≥1 eq, the initial amount of anhydrous formic acid is ≥1.5 eq, and the initial amount of N-methylbenzylamine and anhydrous formic acid is preferably 1.5 eq:2 eq.

[0013] By adjusting the initial feed ratio of N-methylbenzylamine and anhydrous formic acid, the effective conversion rate of the raw material naltrexone to the target product nalfarafen hydrochloride intermediate (Formula III) is maximized while controlling costs.

[0014] In one embodiment of the present invention, N-methylbenzylamine and anhydrous formic acid are added 2-5 times, preferably 3-4 times. Under these reaction conditions, N-methylbenzylamine and anhydrous formic acid readily undergo formylation, producing the impurity methyl-N-benzylformamide, preventing the initial material naltrexone from reacting completely. To improve the conversion rate, multiple additions are used to prevent unreacted N-methylbenzylamine and anhydrous formic acid from preferentially reacting and converting into impurities in the initial stage of the reaction.

[0015] In one embodiment of the present invention, based on the molar amount of naltrexone, the amount of N-methylbenzylamine added is ≥0.2 eq, and the amount of anhydrous formic acid added is ≥0.2 eq.

[0016] In one embodiment of the present invention, the ratio of N-methylbenzylamine to anhydrous formic acid in each feeding is (0.2-0.8 eq):(0.2-0.8 eq), preferably 0.5 eq:0.5 eq.

[0017] In one embodiment of the present invention, the solvent used in the reductive amination reaction can be any one or a combination of toluene, xylene, and ethylbenzene, preferably ethylbenzene. When ethylbenzene is used as the reaction solvent, the reaction temperature is preferably 135–140°C. To reduce the number of solvents introduced, using ethylbenzene, which has a similar boiling point, as the reaction solvent results in a higher degree of reaction.

[0018] The present invention provides a method for preparing nalfarafen hydrochloride, comprising the following steps:

[0019] a. Acyl chloride reaction: The compound shown in formula IV is acyl chlorideed in oxalyl chloride to give the compound shown in formula V.

[0020] b. Hydrogenation-debenzylation reaction: The nalfarafen hydrochloride intermediate shown in Formula III undergoes hydrogenation-debenzylation in glacial acetic acid under palladium-on-carbon catalysis to yield the compound shown in Formula VI.

[0021] c. Condensation reaction: The compound shown in formula V is condensed with the compound shown in formula VI, and the resulting product is the free base of sodium farafen hydrochloride.

[0022] d. Salt formation: Dissolve the free base of nalfarafen hydrochloride in methanol, add hydrochloric acid to form a salt, and then add isopropanol to crystallize and obtain nalfarafen hydrochloride of crystal type A.

[0023] e. Crystallization: Dissolve Nafaprafen hydrochloride (Crystal A) in methanol, filter, concentrate the filtrate, and then slurry with isopropanol to obtain amorphous Nafaprafen hydrochloride.

[0024] The synthesis route is as follows:

[0025]

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1) This invention uses anhydrous formic acid as a hydrogen donor instead of hydrogen donor, thus avoiding the generation of highly toxic cyanide during the reaction process.

[0028] 2) Improve the efficient conversion rate of naltrexone to the nalfarafen hydrochloride intermediate shown in Formula III: An appropriate equivalence ratio can ensure that the reaction proceeds mainly in the direction of generating the target intermediate, reducing unnecessary side reactions and thus reducing the formation of byproducts. For example, avoid non-specific reactions between excess formic acid and solvents or other reactants, thereby improving the efficient conversion rate to the target product nalfarafen hydrochloride intermediate shown in Formula III.

[0029] 3) Improve naltrexone conversion: By repeatedly adding N-methylbenzylamine and formic acid, the optimized equivalent ratio helps to achieve a higher feed conversion rate, that is, more naltrexone is converted into the target intermediate, rather than remaining in an unreacted state or existing as a byproduct.

[0030] 4) Improved product purity: Reduced byproducts mean fewer impurities need to be removed in subsequent purification steps, making it easier to obtain high-purity target intermediates. This provides a more efficient and environmentally friendly synthetic method for the preparation of nalfarafen hydrochloride and its derivatives. Detailed Implementation

[0031] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0032] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0033] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

[0034] The information on starting materials and intermediates involved in this invention is as follows:

[0035] Formula I is naltrexone, with the molecular formula C. 20 H 24 ClNO4 has a molecular weight of 341.41.

[0036] Formula II is N-methylbenzylamine, with the molecular formula C8H. 11 N, with a molecular weight of 121.18.

[0037] The Chinese chemical name for Formula III is (6R)-6-(benzyl(methyl)amino)-17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan, and its molecular formula is C2. 28 H 34 N2O3 has a molecular weight of 446.59.

[0038] The Chinese chemical name of Formula IV is (E)-3-(furan-3-yl)acrylic acid, with the molecular formula C7H6O3 and a molecular weight of 138.12.

[0039] The Chinese chemical name of formula V is (E)-3-(furan-3-yl)acryloyl chloride, with the molecular formula C7H5ClO2 and a molecular weight of 156.57.

[0040] The Chinese chemical name of Formula VI is (6R)-6-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan, abbreviated as 6β-N-methyl-naltrexamine, with the molecular formula C. 21 H 28 N2O3 has a molecular weight of 356.47.

[0041] The present invention provides a method for preparing a nalfarafen hydrochloride intermediate, comprising the following steps:

[0042] A reductive amination reaction was carried out by repeatedly adding N-methylbenzylamine (Formula II) and anhydrous formic acid to naltrexone (Formula I) to generate nalfarafen hydrochloride intermediate (Formula III).

[0043] The synthesis route is as follows:

[0044]

[0045] In one embodiment of the present invention, based on the molar amount of naltrexone, the initial input amount of N-methylbenzylamine is ≥1 eq, and the initial input amount of anhydrous formic acid is ≥1.5 eq. The initial input amount of N-methylbenzylamine can be 1.0 eq, 1.25 eq, 1.5 eq, or 1.8 eq; the initial input ratio of anhydrous formic acid can be 1.5 eq, 2.0 eq, 2.5 eq, or 3.0 eq; preferably 1.5 eq: 2.0 eq.

[0046] In one embodiment of the present invention, N-methylbenzylamine and anhydrous formic acid are added 2-5 times, preferably 3-4 times.

[0047] In one embodiment of the present invention, after the initial raw materials are added, N-methylbenzylamine and anhydrous formic acid are subsequently added. Based on the molar amount of naltrexone, the amount of N-methylbenzylamine added is ≥0.2 eq, and the amount of anhydrous formic acid added is ≥0.2 eq. As long as it is within this range, it is not limited to any specific ratio, for example: 0.5 eq:0.5 eq, 0.2 eq:0.5 eq, 0.8 eq:0.5 eq, 1 eq:0.5 eq, 0.5 eq:0.2 eq, 0.5 eq:0.8 eq, 0.5 eq:1 eq; preferably 0.5 eq:0.5 eq, but not limited thereto. By matching the ratio of the added N-methylbenzylamine to anhydrous formic acid with the aforementioned initial ratio, not only can the conversion rate of the raw material naltrexone be improved, but also the effective conversion rate of naltrexone to the nalfarafen hydrochloride intermediate shown in Formula III can be improved.

[0048] This invention significantly optimizes the synthesis process of nalfarafen hydrochloride intermediate of formula III by precisely adjusting the equivalence ratio of N-methylbenzylamine to anhydrous formic acid. This adjustment not only reduces the formation of byproducts and improves the conversion rate of the target intermediate, but also improves the purity of the product.

[0049] In one embodiment of the present invention, the solvent used in the reductive amination reaction can be any one or a combination of toluene, xylene, and ethylbenzene, preferably ethylbenzene. When ethylbenzene is used as the reaction solvent, the reaction temperature is preferably 135–140°C, and can be 135°C, 138°C, or 140°C. Using ethylbenzene, which has a similar boiling point, as the reaction solvent results in a higher degree of reaction.

[0050] This invention also provides a method for preparing nalfarafen hydrochloride, comprising the following six steps:

[0051] a. Acyl chloride reaction: The compound shown in formula IV is acyl chlorideed in oxalyl chloride to give the compound shown in formula V.

[0052] b. Hydrogenation-debenzylation reaction: The nalfarafen hydrochloride intermediate shown in Formula III undergoes hydrogenation-debenzylation in glacial acetic acid under palladium-on-carbon catalysis to yield the compound shown in Formula VI.

[0053] c. Condensation reaction: The compound shown in formula V is condensed with the compound shown in formula VI, and the resulting product is the free base of sodium farafen hydrochloride.

[0054] d. Salt formation: Dissolve the free base of nalfarafen hydrochloride in methanol, add hydrochloric acid to form a salt, and then add isopropanol to crystallize and obtain nalfarafen hydrochloride of crystal type A.

[0055] e. Crystallization: Dissolve Nafaprafen hydrochloride (Crystal A) in methanol, filter, concentrate the filtrate, and then slurry with isopropanol to obtain amorphous Nafaprafen hydrochloride.

[0056] The synthesis route is as follows:

[0057]

[0058] This invention significantly optimizes the synthesis process of nalfarafen hydrochloride intermediate of Formula III by precisely adjusting the equivalence ratio of N-methylbenzylamine to anhydrous formic acid. This adjustment not only reduces the generation of byproducts and improves the efficient conversion rate of naltrexone to the nalfarafen hydrochloride intermediate of Formula III, but also improves the purity of the product. This invention provides a more efficient and environmentally friendly synthetic method for the preparation of nalfarafen hydrochloride and its derivatives.

[0059] The present invention will be further described in detail below with reference to the embodiments. However, the present invention is not limited to the examples given.

[0060] Example 1

[0061] Step 1)

[0062] Reductive amination reaction:

[0063] Preparation of raw material naltrexone: The starting material naltrexone hydrochloride was purchased from Hainan Manfangyuan Pharmaceutical Co., Ltd., with the molecular formula C 20 H 24 ClNO4, with a molecular weight of 377.87, was prepared by mixing 50.00 g of naltrexone hydrochloride with 750 ml of dichloromethane. Sodium carbonate aqueous solution was added while stirring, and the mixture was allowed to stand. The layers were separated, and the aqueous phase was extracted with dichloromethane. After extraction, the organic phases were combined, and 75.00 g of anhydrous sodium sulfate was added. The mixture was dried, filtered, and the filtrate was concentrated under reduced pressure in a water bath at 30–45 °C, with a vacuum degree ≤ [missing value].

[0064] -0.06 MPa. Concentrate to dryness to obtain 47.45 g of white solid, yielding the raw material naltrexone, which is set aside for later use.

[0065] Add 45.00g of naltrexone to a 1L three-necked flask and attach a water separator. Then add 23.96g of N-methylbenzylamine and 450ml of ethylbenzene sequentially. Purge the mixture with nitrogen three times, and maintain nitrogen pressure throughout the process. Heat the mixture to 138℃, reflux for 30 minutes to separate the water, and then slowly add 12.13g of anhydrous formic acid dropwise at this temperature over approximately 30 minutes. After the addition is complete, maintain the temperature and stir the reaction for 20 minutes.

[0066] Add 7.99 g of N-methylbenzylamine to the reaction solution, stir for 10 minutes, then slowly add 3.03 g of anhydrous formic acid 2 dropwise over a period of 30 minutes. After the addition is complete, stir the reaction solution for 20 minutes. Repeat the above addition operation three times to obtain reaction solution 1.

[0067] A. Formula for calculating naltrexone conversion rate and the effective conversion rate of naltrexone to the nalfarafen hydrochloride intermediate shown in Formula III (hereinafter referred to as effective conversion rate).

[0068] Calculation of naltrexone conversion rate: Conversion rate = 100% - Percentage of naltrexone remaining

[0069] Evaluation revealed that the absorbance values ​​of the various byproduct impurities in the reaction solution were close to those of naltrexone and the nalfarafen hydrochloride intermediate shown in Formula III. HPLC analysis, followed by simple area normalization, yielded an area-normalized percentage of naltrexone that accurately reflected the remaining amount of naltrexone during the reaction. Therefore, those skilled in the art typically use the area-normalized percentage of naltrexone in the reaction solution as the remaining percentage of naltrexone to roughly calculate the conversion rate.

[0070] Effective conversion rate:

[0071] Effective conversion rate = naltrexone conversion rate × area percentage of the nalfarafen hydrochloride intermediate shown in Formula III. In the reaction solution, naltrexone may be converted into other impurities in addition to the naltrexone intermediate shown in Formula III. To more accurately evaluate whether the conversion of naltrexone in this step is an effective conversion, the conversion rate calculated above is multiplied by the area percentage of the nalfarafen hydrochloride intermediate shown in Formula III. The resulting conversion rate is defined as the effective conversion rate of this step.

[0072] B. Detection methods for related substances

[0073] Detection of related substances in the obtained reaction solution 1:

[0074] The determination was performed according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512).

[0075] Solvent: 0.1 mol / L hydrochloric acid solution : acetonitrile (60:40)

[0076] For the test solution, take an appropriate amount of this product, add solvent to dissolve it, and quantitatively dilute it to prepare a solution containing approximately 0.5 mg per 1 ml.

[0077] System suitability solution: Accurately weigh appropriate amounts of impurities naltrexone and N-methylbenzylamine, dissolve and dilute with solvent to prepare a solution containing 0.75 μg of naltrexone and 0.5 mg of N-methylbenzylamine per 1 ml.

[0078] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material (e.g., GL Sciences Inertisl ODS-3 column, 4.6 mm × 250 mm, 5 μm or equivalent column); mobile phase A was 50 mmol / L sodium dihydrogen phosphate solution-acetonitrile (95:5); mobile phase B was 50 mmol / L sodium dihydrogen phosphate solution-acetonitrile (60:40); flow rate was 1.0 mL / min, column temperature was 40 °C, detection wavelength was 210 nm, and injection volume was 20 μL.

[0079] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 35 50 50 45 25 75 45.1 100 0 65 100 0

[0080] Note: If there is gradient peak interference, a ghost peak trapping column (Welch Chost-Buster Column Kits 4.6mm × 50mm or a column with equivalent performance) can be added.

[0081] System suitability requirements: Accurately measure 20 μL of the system suitability solution and inject it into the liquid chromatograph, then record the chromatogram. Naltrexone and N-methylbenzylamine should elute sequentially. The resolution between the main peak and adjacent impurities should be greater than 1.5, and the resolution between impurities should be greater than 1.2.

[0082] For the assay, accurately measure 20 μL of the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0083] Spectrum processing:

[0084] (1) Integrate all impurity peaks in the chromatogram of the test solution except for the blank using the area normalization method. The peak area ratio of impurity naltrexone is the remaining percentage of naltrexone.

[0085] (2) Integrate all impurity peaks in the chromatogram of the test solution except for the blank and YNF-1-IM01 using the area normalization method. The peak area ratio of the nafarafen hydrochloride intermediate shown in Formula III is the area percentage of the nafarafen hydrochloride intermediate.

[0086] Post-processing:

[0087] Cool the above reaction solution 1 to 25℃, add 450ml of purified water, and adjust the pH to 3-4 with 6N hydrochloric acid (preparation method: add an equal volume of purified water to 88ml of concentrated hydrochloric acid and stir for 10 minutes). Heat to 52℃, stir for 10 minutes, and then allow to stand and separate the layers. Extract the aqueous phase twice with ethylbenzene, 225ml each time. After extraction, discard the organic phase. Add 450ml of dichloromethane to the aqueous phase, and while stirring, add sodium carbonate solution (preparation method: add 97.79g of sodium carbonate to 652ml of purified water and stir until dissolved). Adjust the pH to 9-10, continue stirring for 10 minutes, and then allow to stand and separate the layers. Extract the aqueous phase twice with dichloromethane, 225ml each time. Combine the organic phases and concentrate under reduced pressure at 35℃ in a water bath, with a vacuum degree ≤-0.06MPa. After concentration to dryness, a brown solid is obtained, which is the nalfarafen hydrochloride intermediate shown in Formula III.

[0088] Step 2)

[0089] 56.00 g of nalfarafen hydrochloride intermediate (Formula III), 560 ml of glacial acetic acid, and 5.60 g of 10% wet palladium on carbon were added sequentially to a 1 L hydrogenation reactor. After purging the reaction system with hydrogen three times, hydrogen gas was introduced to a pressure of 0.4–0.5 MPa, and the temperature was raised to 80 ± 5 °C. The reaction was carried out at a pressure of 0.4–0.5 MPa, and the nalfarafen hydrochloride intermediate (Formula III) underwent hydrogenation and debenzylation to obtain the compound (Formula VI).

[0090] Step 3)

[0091] Add 12.20 g of the compound shown in Formula IV, 73.20 g of oxaloyl chloride, and 0.30 g of N,N-dimethylformamide sequentially to a 500 ml single-necked flask. Heat to 55–65 °C and stir for 30 minutes. Cool down and concentrate the reaction solution under reduced pressure in a water bath at 40–50 °C with a vacuum degree ≤ -0.08 MPa. After concentrating to dryness, add 151 ml of dichloromethane and stir to dissolve, obtaining a dichloromethane solution of the compound shown in Formula V, for later use.

[0092] Step 4)

[0093] Add 305 ml of dichloromethane and 30.50 g of the compound shown in Formula VI to a three-necked flask in sequence, stir and cool to 0-5°C, and slowly add the above solution dropwise while controlling the temperature at 0-10°C. After the addition is complete, continue stirring at 0-10°C for 30 minutes to carry out the condensation reaction.

[0094] Step 5)

[0095] Salt formation: Add 41.00g of nalfarafen hydrochloride free base and 410ml of methanol to a 2L single-necked flask, then add 46ml of 2N hydrochloric acid (preparation method: mix 8ml of concentrated hydrochloric acid and 40ml of purified water). Dissolve the system completely, add 2.00g of activated carbon for decolorization for 30min, filter, and transfer the filtrate to a constant pressure dropping funnel for later use.

[0096] Recrystallization: In another 2L three-necked flask, add 1025ml of isopropanol and 0.40g of A-type seed crystals. Add the methanol solution from the previous step to the isopropanol and stir at 10-15℃ for 24 hours to allow crystals to precipitate. Filter and wash with 205ml of isopropanol to obtain A-type nalfarafen hydrochloride.

[0097] Step 6)

[0098] Crystallization: The wet product was dissolved in 246 ml of anhydrous methanol and concentrated under reduced pressure in a water bath at 40–50 °C with a vacuum degree ≤ -0.08 MPa until dry. The solid was transferred to a vacuum drying oven and dried under reduced pressure at 50 ± 5 °C with a vacuum degree ≤ -0.08 MPa until constant weight, yielding amorphous nalfarafen hydrochloride.

[0099] Examples 2-4

[0100] The only difference between Examples 2-4 and Example 1 is that, based on the molar amount of naltrexone, the initial amount of N-methylbenzylamine added in the initial feed of N-methylbenzylamine and anhydrous formic acid is different, but all are ≥1 eq. In Example 2, the initial molar ratio of N-methylbenzylamine is 1.25 eq, corresponding to an initial feed of 19.97 g of N-methylbenzylamine; in Example 3, the initial molar ratio of N-methylbenzylamine is 1.0 eq, corresponding to an initial feed of 15.97 g of N-methylbenzylamine; in Example 4, the initial molar ratio of N-methylbenzylamine is 1.8 eq, corresponding to an initial feed of 28.75 g of N-methylbenzylamine. Detailed data are shown in Table 1 below. Apart from this, all other reaction conditions are the same as in Example 1, and the reaction solutions 2-4 containing the nalfarafen hydrochloride intermediate shown in Formula III are obtained in the corresponding step 1).

[0101] Examples 5-7

[0102] The only difference between Examples 5-7 and Example 1 is that, based on the molar amount of naltrexone, the initial amount of anhydrous formic acid in the initial feed of N-methylbenzylamine and anhydrous formic acid is different, but all are ≥1.5 eq. In Example 5, the initial molar ratio of anhydrous formic acid is 1.5 eq, and the corresponding initial feed of N-methylbenzylamine is 9.10 g; in Example 6, the initial molar ratio of anhydrous formic acid is 2.5 eq, and the corresponding initial feed of N-methylbenzylamine is 15.17 g; in Example 7, the initial molar ratio of anhydrous formic acid is 3.0 eq, and the corresponding initial feed of N-methylbenzylamine is 18.20 g. Detailed data are shown in Table 1 below. Apart from this, all other reaction conditions are the same as in Example 1, and the reaction solutions 5-7 containing the nalfarafen hydrochloride intermediate shown in Formula III are obtained in the corresponding step 1).

[0103] Examples 8-10

[0104] The only difference between Examples 8-10 and Example 1 is that, based on the molar amount of naltrexone, the amount of N-methylbenzylamine added in each supplementary feeding of N-methylbenzylamine and anhydrous formic acid varies, but is always ≥0.2 eq. In Example 8, the amount of N-methylbenzylamine added each time is 0.2 eq, corresponding to 3.19 g; in Example 9, the amount of N-methylbenzylamine added each time is 0.8 eq, corresponding to 12.78 g; in Example 10, the amount of N-methylbenzylamine added each time is 1.0 eq, corresponding to 15.97 g. Detailed data are shown in Table 1 below. Apart from this, all other reaction conditions are the same as in Example 1, and the reaction solutions 8-10 containing the nalfarafen hydrochloride intermediate shown in Formula III are obtained in the corresponding step 1).

[0105] Examples 11-13

[0106] The only difference between Examples 11-13 and Example 1 is that, based on the molar amount of naltrexone, the amount of anhydrous formic acid added in each supplementary feeding of N-methylbenzylamine and anhydrous formic acid varies, but is always ≥0.2 eq. In Example 11, the amount of anhydrous formic acid added each time is 0.2 eq, corresponding to 1.21 g; in Example 12, the amount of anhydrous formic acid added each time is 0.8 eq, corresponding to 4.85 g; in Example 13, the amount of anhydrous formic acid added each time is 1.0 eq, corresponding to 6.07 g. Detailed data are shown in Table 1 below. Apart from this, all other reaction conditions are the same as in Example 1, resulting in reaction solutions 11-13 containing the nalfarafen hydrochloride intermediate shown in Formula III obtained in the corresponding step 1).

[0107] Comparative Example 1

[0108] The difference between Comparative Example 1 and Examples 1-4 lies in the initial input of N-methylbenzylamine and anhydrous formic acid. Based on the molar amount of naltrexone, the initial input of N-methylbenzylamine differs. In Comparative Example 1, the initial input of N-methylbenzylamine is <1 eq. In Comparative Example 1, the initial input of N-methylbenzylamine is 0.8 eq, corresponding to an initial input of 12.78 g. Detailed data are shown in Table 1 below. Apart from this, the other reaction conditions are the same as in Examples 1-4, and the reaction solution 14 containing the nalfarafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0109] Comparative Example 2

[0110] The only difference between Comparative Example 2 and Examples 5-7 is the initial amount of anhydrous formic acid added, based on the molar amount of naltrexone. In Comparative Example 2, the initial amount of anhydrous formic acid is <1.5 eq, while in Comparative Example 2, the initial amount of anhydrous formic acid is 1.1 eq, corresponding to 6.67 g. Detailed data can be found in Table 1 below. Apart from this, the other reaction conditions are the same as in Examples 5-7, and the reaction solution 15 containing the nalfarafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0111] Comparative Example 3

[0112] The only difference between Comparative Example 3 and Examples 8-10 is that, based on the molar amount of naltrexone, the amount of N-methylbenzylamine added each time in the supplementary addition of N-methylbenzylamine and anhydrous formic acid is different. In Comparative Example 3, the amount of N-methylbenzylamine added each time is <0.2 eq, while in Comparative Example 3, the amount of N-methylbenzylamine added each time is 0.1 eq, corresponding to 1.60 g of N-methylbenzylamine added each time. Detailed data are shown in Table 1 below. Apart from this, the other reaction conditions are the same as in Examples 8-10, and the reaction solution 16 containing the nalfarafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0113] Comparative Example 4

[0114] The only difference between Comparative Example 4 and Examples 11-13 is that, in the addition of N-methylbenzylamine and anhydrous formic acid, the amount of anhydrous formic acid added each time is different based on the molar amount of naltrexone, with each addition of anhydrous formic acid being <0.2 eq. In Comparative Example 4, the amount of anhydrous formic acid added each time is 0.1 eq, corresponding to 0.61 g of anhydrous formic acid added each time. Detailed data are shown in Table 1 below. Apart from this, the other reaction conditions are the same as in Examples 11-13, and the reaction solution 17 containing the nalfarafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0115] Comparative Example 5

[0116] Comparative Example 5, based on the molar amount of naltrexone, the initial feed amounts of N-methylbenzylamine and anhydrous formic acid were <1 eq and ≥1.5 eq, respectively. For subsequent additions of N-methylbenzylamine and anhydrous formic acid, the amount of N-methylbenzylamine added each time was ≥0.2 eq and the amount of anhydrous formic acid added each time was ≥0.2 eq. Detailed data are shown in Table 1 below. Except for these, the other reaction conditions were the same as in Example 1, resulting in reaction solution 18 containing the nalfarafen hydrochloride intermediate shown in Formula III, obtained in the corresponding step 1).

[0117] Comparative Example 6

[0118] Comparative Example 6, based on the molar amount of naltrexone, the initial feed amounts of N-methylbenzylamine and anhydrous formic acid were <1 eq and ≥1.5 eq, respectively; the supplementary feed amounts of N-methylbenzylamine and anhydrous formic acid were <0.2 eq and ≥0.2 eq, respectively; detailed data are shown in Table 1 below. Except for this, the other reaction conditions were the same as in Example 1, and the reaction solution 19 containing the nalfarafen hydrochloride intermediate shown in Formula III was obtained in the corresponding step 1).

[0119] Comparative Example 7

[0120] The difference between Comparative Example 7 and Example 1 is that the total amount of N-methylbenzylamine and anhydrous formic acid is the same, but Comparative Example 7 is added once, while Example 1 is added multiple times. For detailed data, please refer to Table 1 below. Apart from this, the other reaction conditions are the same as those in Example 1. The reaction solution 20 containing the nalfarafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0121] Comparative Example 8

[0122] Referring to the preparation method of compound III shown in the "Improved Synthesis Process of Nafrapne Hydrochloride" published in the Chinese Journal of Medicinal Chemistry by Lunan Pharmaceutical Group Co., Ltd., Shandong New Era Pharmaceutical Co., Ltd., and the National Engineering Research Center for Chiral Pharmaceuticals, the reaction solution 21 containing the intermediate nafrapne hydrochloride shown in Formula III was prepared by this method.

[0123] The key raw materials and key reaction conditions for each embodiment and comparative example are shown in Table 1 below:

[0124] Table 1. Key materials and reaction conditions for the intermediate of nalfarafen hydrochloride shown in Formula III.

[0125]

[0126]

[0127] The contents of naltrexone and nalfarafen hydrochloride intermediate shown in Formula III in reaction solutions 1-21 were detected according to the detection method described in Example 1. The detection results and the conversion rate and effective conversion rate of naltrexone under each reaction condition are shown in Table 2.

[0128] Table 2 shows the percentage of naltrexone remaining in reaction solution 1-21, the content of nalfarafen hydrochloride intermediate shown in Formula III, the conversion rate of naltrexone, and the effective conversion rate of naltrexone determined by HPLC.

[0129]

[0130]

[0131] From Table 2, the following conclusions can be drawn:

[0132] Comparing reaction solutions 1-4 and reaction solution 14, it can be seen that the conversion rate of naltrexone in Examples 1-4 all reached over 90%, while the conversion rate of naltrexone in Comparative Example 1 was less than 90%. Furthermore, the effective conversion rate of naltrexone in Examples 1-4 was significantly higher than that in Comparative Example 1. Therefore, under the same conditions, changing the initial feed amount of N-methylbenzylamine significantly affected the conversion rate and effective conversion rate of naltrexone. When the initial feed amount of N-methylbenzylamine was greater than or equal to 1.0 eq, the conversion rate and effective conversion rate of naltrexone were higher, especially when the initial feed amount of N-methylbenzylamine was 1.5 eq, the conversion rate and effective conversion rate of naltrexone were the highest.

[0133] Comparing reaction solutions 1, 5-7, and 15, it can be seen that the conversion rate of naltrexone in Examples 1 and 5-7 both reached over 90%, while the conversion rate of naltrexone in Comparative Example 2 was only 80.52%. Furthermore, the effective conversion rate of naltrexone in Examples 1 and 5-7 was significantly higher than that in Comparative Example 2. Therefore, under the same conditions, changing the initial feed amount of anhydrous formic acid significantly affected the conversion rate and effective conversion rate of naltrexone. When the initial feed amount of anhydrous formic acid was greater than or equal to 1.5 eq, the conversion rate and effective conversion rate of naltrexone were even higher.

[0134] Comparing reaction solutions 1, 8-10, and 16, it can be seen that the conversion rate of naltrexone in Examples 1 and 8-10 both reached over 90%, while the conversion rate of naltrexone in Comparative Example 3 was less than 90%. Furthermore, the effective conversion rate of naltrexone in Examples 1 and 8-10 was significantly higher than that in Comparative Example 3. Therefore, under the same conditions, changing the amount of N-methylbenzylamine added significantly affected the conversion rate and effective conversion rate of naltrexone. When the amount of N-methylbenzylamine added was greater than or equal to 0.2 eq, the conversion rate and effective conversion rate of naltrexone were even higher.

[0135] Comparing reaction solutions 1, 11-13, and 17, it can be seen that the conversion rate of naltrexone in Examples 1 and 11-13 both reached over 90%, while the conversion rate of naltrexone in Comparative Example 4 was less than 90%. Furthermore, the effective conversion rate of naltrexone in Examples 1 and 11-13 was significantly higher than that in Comparative Example 4. Therefore, under the same conditions, changing the amount of anhydrous formic acid added significantly affected the conversion rate and effective conversion rate of naltrexone. When the amount of anhydrous formic acid added was greater than or equal to 0.2 eq, the conversion rate and effective conversion rate of naltrexone were even higher.

[0136] Comparing reaction solutions 1-13 and reaction solutions 18, 19, and 20, it is evident that the conversion rate of naltrexone in Examples 1-13 all reached over 90%, while the conversion rate of naltrexone in Comparative Examples 5, 6, and 7 was less than 90%. Furthermore, the effective conversion rate of naltrexone in Examples 1-13 was significantly higher than that in Comparative Examples 5, 6, and 7. Therefore, under the same conditions, when N-methylbenzylamine and anhydrous formic acid are added multiple times, with an initial input of N-methylbenzylamine ≥ 1 eq and an initial input of anhydrous formic acid ≥ 1.5 eq, and subsequent supplementary inputs of N-methylbenzylamine ≥ 0.2 eq and anhydrous formic acid ≥ 0.2 eq, the conversion rate and effective conversion rate of naltrexone are even higher.

[0137] Comparing reaction solutions 1-13 and reaction solution 21, it can be seen that the effective conversion rate of naltrexone in Examples 1-13 all exceeds 80%, while the effective conversion rate of naltrexone in Comparative Example 8 is only 61.46%. Therefore, the technical solution provided by the present invention significantly improves the effective conversion rate of naltrexone.

[0138] It is understood that the above embodiments are merely exemplary implementations used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A method for preparing a sodium farafen hydrochloride intermediate, characterized in that, include: By repeatedly adding N-methylbenzylamine (Formula II) and anhydrous formic acid to naltrexone (Formula I) as shown in Formula I, a reductive amination reaction is carried out to obtain nalfarafen hydrochloride intermediate (Formula III). The synthesis route is as follows: ； Based on the molar amount of naltrexone, the initial addition ratio of N-methylbenzylamine to anhydrous formic acid is 1.5 eq: 2 eq. The N-methylbenzylamine and the anhydrous formic acid are added 3-4 times. The ratio of N-methylbenzylamine to anhydrous formic acid added is (0.5-0.8 eq):(0.5-0.8 eq).

2. The method for preparing the sodium farafen hydrochloride intermediate according to claim 1, wherein, The solvent used in the reductive amination reaction is any one or a combination of toluene, xylene, and ethylbenzene.

3. The method for preparing the sodium farafen hydrochloride intermediate according to claim 2, wherein, When ethylbenzene is selected as the solvent, the reaction temperature is 135~140℃.

4. A method for preparing nalfarafen hydrochloride, characterized in that, This method uses the method described in any one of claims 1 to 3 to prepare the sodium farafen hydrochloride intermediate; Furthermore, nalfarafen hydrochloride was prepared using this intermediate as a raw material. Includes the following steps: a. Acyl chloride reaction: The compound shown in formula IV is acylated in oxalyl chloride to give the compound shown in formula V. b. Hydrogenation and debenzylation reaction: The nalfarafen hydrochloride intermediate shown in Formula III is hydrogenated and debenzylated in glacial acetic acid under palladium-on-carbon catalysis to give the compound shown in Formula VI. c. Condensation reaction: The compound shown in formula V is condensed with the compound shown in formula VI, and the resulting product is the free base of sodium farafen hydrochloride. d. Salt formation: Dissolve the free base of nalfarafen hydrochloride in methanol, add hydrochloric acid to form a salt, and then add isopropanol to crystallize and obtain nalfarafen hydrochloride of crystal type A. e. Crystallization: Dissolve Nafaprafen hydrochloride (Crystal A) in methanol, filter, concentrate the filtrate, and then slurry with isopropanol to obtain amorphous Nafaprafen hydrochloride. The synthesis route is as follows: 。

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