Natartafene hydrochloride intermediate and preparation method thereof

Abstract

The invention discloses a preparation method of a natamaran hydrochloride intermediate, which comprises the following steps: repeatedly adding N-methylbenzylamine shown in a formula II and anhydrous formic acid into naltrexone shown in a formula I for reductive amination reaction to generate the natamaran hydrochloride intermediate shown in a formula III, the synthesis route is as follows: # imgabs0 obviously improves the reaction conversion rate of a raw material naltrexone and the effective conversion rate of converting the raw material naltrexone into a target product naarafarene hydrochloride intermediate shown as a formula III.

Description

Technical Field

[0001] The present application belongs to the technical field of drug synthesis, and specifically relates to a method for preparing a nalfarapine hydrochloride intermediate. Background Art

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

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

[0004]

[0005] This technical route adopts the method for preparing the nalfafen hydrochloride intermediate shown in formula III: naltrexone hydrochloride is desalted to generate naltrexone, and then naltrexone undergoes a reductive amination reaction with N-methylbenzylamine. Although the conversion rate of the raw material naltrexone is high in this process, sodium cyanoborohydride is used as a hydrogen donor to generate highly toxic cyanide, which is highly dangerous. There are many impurities generated after reduction, and the effective conversion rate of the target product nalfafen hydrochloride intermediate shown in formula III is too low, and wastewater treatment is difficult, which makes it difficult to achieve industrial scale-up production. As a key intermediate for synthesizing nalfafen hydrochloride, the yield and purity of the nalfafen hydrochloride intermediate shown in formula III directly affect the quality and market supply capacity of the drug. Therefore, it is still a problem that technicians in this field need to solve to explore a safe and environmentally friendly method that improves the effective conversion rate of the raw material naltrexone into the target product nalfafen hydrochloride intermediate shown in formula III while having a high conversion rate of the raw material naltrexone. Summary of the invention

[0006] In order to solve the above problems, the present application provides a method for preparing a nalfafen hydrochloride intermediate, which significantly improves the reaction conversion rate of the raw material naltrexone and the effective conversion rate of the nalfafen hydrochloride intermediate into the target product shown in Formula III.

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

[0008] Adding N-methylbenzylamine and anhydrous formic acid of formula II to naltrexone of formula I multiple times to carry out a reductive amination reaction to generate a nalfafen hydrochloride intermediate of formula III,

[0009] The synthetic route is as follows:

[0010]

[0011] The present invention uses anhydrous formic acid as a hydrogen donor, and the anhydrous formic acid is cracked into hydrogen and carbon dioxide under high temperature conditions, thereby avoiding the generation of highly toxic cyanide. In addition, the reductive amination reaction is a reversible reaction, and the water generated in the reaction needs to be removed by atmospheric distillation during the reaction, and N-methylbenzylamine and anhydrous formic acid are repeatedly added multiple times, which can improve the conversion rate of the raw material naltrexone and the effective conversion rate of the naltrexone hydrochloride intermediate shown in formula III.

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

[0013] By adjusting the initial feed ratio of N-methylbenzylamine and anhydrous formic acid, the effective conversion rate of the raw material naltrexone into the target product nalfafen hydrochloride intermediate shown in formula III can be maximized under the premise of controlling the cost.

[0014] In one embodiment of the present invention, N-methylbenzylamine and anhydrous formic acid are added 2-5 times, preferably 3-4 times. N-methylbenzylamine and anhydrous formic acid are prone to formylation reaction under the reaction conditions to produce impurity methyl-N-benzylformamide, and the starting material naltrexone cannot react completely. In order to improve the conversion rate, multiple additions are used to avoid the unreacted N-methylbenzylamine and anhydrous formic acid in the initial stage of the reaction from preferentially reacting and converting into impurities.

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

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

[0017] In one embodiment of the present invention, the solvent used in the reductive amination reaction can be any one of toluene, xylene, and ethylbenzene or a combination of multiple thereof, preferably ethylbenzene. When ethylbenzene is used as the reaction solvent, the reaction temperature is preferably 135 to 140° C. In order to reduce the types of solvents introduced, ethylbenzene with a similar boiling point is used as the reaction solvent, and the reaction degree is higher.

[0018] The present invention provides a method for preparing nalfarapine hydrochloride, the steps of which are as follows:

[0019] a. Acid chloride reaction: The compound represented by formula IV is chlorinated in oxalyl chloride to obtain the compound represented by formula V,

[0020] b. Hydrogenation debenzylation reaction: The intermediate of nalfafen hydrochloride shown in Formula III is hydrogenated and debenzylated in glacial acetic acid under the catalysis of palladium on carbon to obtain the compound shown in Formula VI.

[0021] c. Condensation reaction: The compound represented by formula V and formula VI is condensed to obtain nalfarapine hydrochloride free base of formula,

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

[0023] e. Crystallization: Dissolve the A-type nalfarapine hydrochloride in methanol, filter, concentrate the filtrate and slurry it with isopropanol to obtain amorphous nalfarapine hydrochloride.

[0024] The synthetic route is as follows:

[0025]

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

[0027] 1) The present invention adopts anhydrous formic acid as a hydrogen donor to avoid the generation of highly toxic cyanide during the reaction.

[0028] 2) Improving the effective conversion rate of naltrexone to the intermediate of nalfafen hydrochloride shown in Formula III: The appropriate equivalent ratio can ensure that the reaction mainly proceeds in the direction of generating the target intermediate, reducing unnecessary side reactions, thereby reducing the generation of by-products. For example, avoiding non-specific reactions of excess formic acid with solvents or other reactants, thereby improving the effective conversion rate of the intermediate of nalfafen hydrochloride shown in Formula III.

[0029] 3) Improving the conversion rate of naltrexone: By repeatedly adding N-methylbenzylamine and formic acid, the optimized equivalent ratio helps to achieve a higher raw material conversion rate, that is, more naltrexone is converted into the target intermediate instead of remaining in an unreacted state or existing in the form of a by-product.

[0030] 4) Improve product purity: Reducing by-products means that fewer impurities need to be removed in the subsequent purification steps, making it easier to obtain high-purity target intermediates. This provides a more efficient and environmentally friendly synthesis method for the preparation of nalfarapine hydrochloride and its derivatives. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present application are clearly described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0032] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship.

[0033] The present application is not limited to the above-mentioned specific implementation modes, which are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

[0034] The information of starting materials and intermediates involved in the present invention is as follows:

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

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

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

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

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

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

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

[0042] N-methylbenzylamine and anhydrous formic acid are added to naltrexone of formula I multiple times to carry out a reductive amination reaction to generate a nalfafen hydrochloride intermediate of formula III.

[0043] The synthetic 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 additional amount of N-methylbenzylamine is ≥ 0.2eq, and the additional amount of anhydrous formic acid is ≥ 0.2eq. As long as it is within this range, it is not limited to any ratio, for example: 0.5eq: 0.5eq, 0.2eq: 0.5eq, 0.8eq: 0.5eq, 1eq: 0.5eq, 0.5eq: 0.2eq, 0.5eq: 0.8eq, 0.5eq: 1eq; preferably 0.5eq: 0.5eq, but not limited thereto. By matching the feed ratio of the additional N-methylbenzylamine and anhydrous formic acid with the aforementioned initial feed ratio, not only the conversion rate of the raw material naltrexone can be improved, but also the effective conversion rate of naltrexone into the nalfafen hydrochloride intermediate shown in Formula III can be improved.

[0048] The present invention can significantly optimize the synthesis process of the nalfarapine hydrochloride intermediate of formula III by accurately adjusting the equivalent ratio of N-methylbenzylamine to anhydrous formic acid. This adjustment not only reduces the generation of by-products, increases 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 of toluene, xylene, and ethylbenzene, or a combination of multiple thereof, preferably ethylbenzene. When ethylbenzene is used as the reaction solvent, the reaction temperature is preferably 135 to 140° C., and can be 135° C., 138° C., or 140° C. When ethylbenzene having a similar boiling point is used as the reaction solvent, the reaction degree is higher.

[0050] The present invention also provides a method for preparing nalfarapine hydrochloride, comprising the following six steps:

[0051] a. Acid chloride reaction: The compound represented by formula IV is chlorinated in oxalyl chloride to obtain the compound represented by formula V,

[0052] b. Hydrogenation debenzylation reaction: The intermediate of nalfafen hydrochloride shown in Formula III is hydrogenated and debenzylated in glacial acetic acid under the catalysis of palladium on carbon to obtain the compound shown in Formula VI.

[0053] c. Condensation reaction: The compound represented by formula V and formula VI is condensed to obtain nalfarapine hydrochloride free base of formula,

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

[0055] e. Crystallization: Dissolve the A-type nalfarapine hydrochloride in methanol, filter, concentrate the filtrate and slurry it with isopropanol to obtain amorphous nalfarapine hydrochloride.

[0056] The synthetic route is as follows:

[0057]

[0058] The present invention can significantly optimize the synthesis process of the nalfafen hydrochloride intermediate of formula III by accurately adjusting the equivalent ratio of N-methylbenzylamine to anhydrous formic acid. This adjustment not only reduces the generation of by-products, but also increases the effective conversion rate of naltrexone into the nalfafen hydrochloride intermediate of formula III, and also improves the purity of the product. This invention provides a more efficient and environmentally friendly synthesis method for the preparation of nalfafen hydrochloride and its derivatives.

[0059] The present invention is further described in detail below in conjunction with the examples, but 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, molecular weight is 377.87, take 50.00g naltrexone hydrochloride and 750ml dichloromethane, add sodium carbonate aqueous solution under stirring, let stand after stirring, separate the liquids, and then extract the aqueous phase with dichloromethane. After the extraction is completed, combine the organic phases, add 75.00g anhydrous sodium sulfate, dry, filter, and concentrate the filtrate under reduced pressure in a water bath at 30-45℃, and the vacuum degree is ≤

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

[0065] 45.00g of naltrexone was added to a 1L three-necked flask and a water separator was installed. Then 23.96g of N-methylbenzylamine and 450ml of ethylbenzene were added in sequence. The nitrogen was replaced three times, and nitrogen was introduced throughout the process for protection. The temperature was raised to 138°C, refluxed and separated for 30 minutes, and then 12.13g of anhydrous formic acid was slowly added dropwise at this temperature. The addition time was controlled to be about 30 minutes. After the addition was completed, the reaction was stirred and kept warm for 20 minutes.

[0066] 7.99 g of N-methylbenzylamine was added to the reaction solution, stirred for 10 minutes, and then 3.03 g of anhydrous formic acid 2 was slowly added dropwise, and the addition time was controlled to be 30 minutes. After the addition was completed, the reaction was stirred for 20 minutes. The above addition operation was repeated 3 times to obtain a reaction solution 1.

[0067] A. Calculation formula of naltrexone conversion rate and effective conversion rate of naltrexone to the nalfafen hydrochloride intermediate shown in formula III (hereinafter referred to as effective conversion rate)

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

[0069] After evaluation, the absorbance values ​​of the by-product impurities in the reaction solution are close to those of naltrexone and the nalfafen hydrochloride intermediate shown in Formula III. After the results of HPLC detection are processed by a simple area normalization method, the obtained area normalized percentage of naltrexone can more accurately reflect the remaining amount of naltrexone in the reaction process. Therefore, those skilled in the art usually use the area normalized percentage of naltrexone in the reaction solution as the remaining percentage of naltrexone, and then roughly calculate the conversion rate of naltrexone.

[0070] Effective conversion rate:

[0071] Effective conversion rate = naltrexone conversion rate × area percentage of the nalfarapine hydrochloride intermediate shown in Formula III In the reaction solution, naltrexone may be converted into other impurities in addition to being converted into the nalfarapine hydrochloride intermediate shown in Formula III. In order to more accurately evaluate whether the conversion of naltrexone in this step is an effective conversion, the conversion rate calculated by the above formula is multiplied by the area percentage of the nalfarapine hydrochloride intermediate shown in Formula III, and 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] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

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

[0076] Take an appropriate amount of the product in the test solution, add solvent to dissolve it and quantitatively dilute it to make a solution containing about 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] The chromatographic conditions are as follows: octadecylsilane bonded silica gel is used as the filler (such as GL Sciences Inertisl ODS-3 column, 4.6 mm × 250 mm, 5 μm or a chromatographic column with equivalent performance); 50 mmol / L sodium dihydrogen phosphate solution-acetonitrile (95:5) is used as the mobile phase A; 50 mmol / L sodium dihydrogen phosphate solution-acetonitrile (60:40) is used as the mobile phase B; the flow rate is 1.0 ml / min, the column temperature is 40°C, the detection wavelength is 210 nm, and the injection volume is 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, add a ghost peak trapping column (Welch Chost-Buster Column Kits 4.6mm×50mm or a chromatographic column with equivalent performance)

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

[0082] Determination method: Accurately measure 20 μL of the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0083] Spectrum processing:

[0084] (1) All impurity peaks except the blank in the chromatogram of the test solution are integrated by the area normalization method, and the peak area ratio of the impurity naltrexone is the residual percentage of naltrexone;

[0085] (2) All impurity peaks except blank and YNF-1-IM01 in the chromatogram of the test solution are integrated by the area normalization method, and the peak area ratio of the nalfarapine hydrochloride intermediate shown in Formula III is the area percentage of the nalfarapine hydrochloride intermediate;

[0086] Post-processing:

[0087] The reaction solution 1 was cooled to 25°C, 450ml of purified water was added, and the pH value was adjusted 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), and the temperature was raised to 52°C. After stirring for 10 minutes, the solution was allowed to stand for separation. The aqueous phase was extracted twice with ethylbenzene, 225ml each time. After the extraction was completed, the organic phase was discarded. 450ml of dichloromethane was added to the aqueous phase, and sodium carbonate solution was added under stirring (preparation method: add 97.79g of sodium carbonate to 652ml of purified water and stir until dissolved), the pH was adjusted to 9-10, and stirring was continued for 10 minutes, and the solution was allowed to stand for separation. The aqueous phase was extracted twice with dichloromethane, 225ml each time. The organic phases were combined, and the water bath was controlled to be 35°C and concentrated under reduced pressure, and the vacuum degree was ≤-0.06MPa. After concentration to dryness, a brown solid was obtained, which was the intermediate of nalfafen hydrochloride shown in formula III.

[0088] Step 2)

[0089] In a 1L hydrogenation reactor, the intermediate of nalfarapine hydrochloride (56.00 g), 560 ml of glacial acetic acid and 5.60 g of 10% wet palladium carbon were added in sequence. After hydrogen was replaced with hydrogen for 3 times, hydrogen was introduced to a pressure of 0.4-0.5 MPa, and the temperature was raised to 80±5° C. The pressure was controlled to 0.4-0.5 MPa for the reaction, and the intermediate of nalfarapine hydrochloride shown in formula III was hydrogenated and debenzylated to obtain a compound shown in formula VI.

[0090] Step 3)

[0091] Add 12.20g of the compound represented by formula IV, 73.20g of oxalyl chloride and 0.30g of N,N-dimethylformamide to a 500ml single-mouth bottle, heat to 55-65°C, and stir to react for 30 minutes. Cool down, and concentrate the reaction solution under reduced pressure at a vacuum degree of ≤-0.08MPa in a water bath at 40-50°C. After concentrating to dryness, add 151ml of dichloromethane and stir to dissolve to obtain a dichloromethane solution of the compound represented by formula V, which is set aside.

[0092] Step 4)

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

[0094] Step 5)

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

[0096] Recrystallization: In another 2L three-necked flask, add 1025ml of isopropanol and 0.40g of crystal type A seed crystal, add the methanol solution in the previous step to the isopropanol, control the temperature at 10-15°C, stir and crystallize for 24h. Filter, rinse with 205ml of isopropanol, and obtain crystal type A nalfafen hydrochloride.

[0097] Step 6)

[0098] Crystallization: After the wet product is dissolved in 246 ml of anhydrous methanol, it is concentrated under reduced pressure in a water bath at 40-50°C, with a vacuum degree of ≤-0.08 MPa, and concentrated to dryness under reduced pressure. The solid is transferred to a vacuum drying oven and dried under reduced pressure to constant weight at 50±5°C and a vacuum degree of ≤-0.08 MPa to obtain amorphous nalfarapine hydrochloride.

[0099] Embodiments 2 to 4

[0100] The difference between Examples 2 to 4 and Example 1 is that in the initial feeding of N-methylbenzylamine and anhydrous formic acid, the initial feeding amount of N-methylbenzylamine is different based on the molar amount of naltrexone, and all are ≥1eq. In Example 2, the initial feeding molar ratio of N-methylbenzylamine is 1.25eq, and the corresponding initial feeding amount of N-methylbenzylamine is 19.97g; in Example 3, the initial feeding molar ratio of N-methylbenzylamine is 1.0eq, and the corresponding initial feeding amount of N-methylbenzylamine is 15.97g; in Example 4, the initial feeding molar ratio of N-methylbenzylamine is 1.8eq, and the corresponding initial feeding amount of N-methylbenzylamine is 28.75g, respectively. For detailed data, see Table 1 below. In addition, the other reaction conditions are the same as in Example 1, and the reaction solution 2-4 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0101] Embodiment 5-7

[0102] The difference between Example 5-7 and Example 1 is that in the initial feed of N-methylbenzylamine and anhydrous formic acid, the initial input amount of anhydrous formic acid is different based on the molar amount of naltrexone, and both are ≥1.5eq. In Example 5, the initial feed molar ratio of anhydrous formic acid is 1.5eq, and the corresponding initial feed of N-methylbenzylamine is 9.10g; in Example 6, the initial feed molar ratio of anhydrous formic acid is 2.5eq, and the corresponding initial feed of N-methylbenzylamine is 15.17g; in Example 7, the initial feed molar ratio of anhydrous formic acid is 3.0eq, and the corresponding initial feed of N-methylbenzylamine is 18.20g, respectively. For detailed data, see Table 1 below. In addition, the other reaction conditions are the same as in Example 1, and the reaction solution 5-7 containing the nalafarafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0103] Examples 8-10

[0104] The difference between Example 8-10 and Example 1 is that in the additional addition of N-methylbenzylamine and anhydrous formic acid, the additional amount of N-methylbenzylamine added each time is different based on the molar amount of naltrexone, and all are ≥0.2eq. In Example 8, the additional amount of N-methylbenzylamine added each time is 0.2eq, and the corresponding additional amount of N-methylbenzylamine added each time is 3.19g; in Example 9, the additional amount of N-methylbenzylamine added each time is 0.8eq, and the corresponding additional amount of N-methylbenzylamine added each time is 12.78g; in Example 10, the additional amount of N-methylbenzylamine added each time is 1.0eq, and the corresponding additional amount of N-methylbenzylamine added each time is 15.97g, and the detailed data is shown in Table 1 below. In addition, the other reaction conditions are the same as those in Example 1, and the reaction solution 8-10 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0105] Examples 11-13

[0106] The difference between Examples 11-13 and Example 1 is that, in the additional 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, and all are ≥0.2eq. In Example 11, the additional amount of anhydrous formic acid added each time is 0.2eq, and the corresponding additional amount of anhydrous formic acid added each time is 1.21g; in Example 12, the additional amount of anhydrous formic acid added each time is 0.8eq, and the corresponding additional amount of anhydrous formic acid added each time is 4.85g; in Example 13, the additional amount of anhydrous formic acid added each time is 1.0eq, and the corresponding additional amount of anhydrous formic acid added each time is 6.07g, and the detailed data is shown in Table 1 below. In addition, the other reaction conditions are the same as those in Example 1, and the reaction solution 11-13 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0107] Comparative Example 1

[0108] The difference between Comparative Example 1 and Examples 1-4 is that in the initial feeding of N-methylbenzylamine and anhydrous formic acid, the initial input amount of N-methylbenzylamine is different based on the molar amount of naltrexone, and the initial input amount of N-methylbenzylamine is <1eq. In Comparative Example 1, the initial input amount of N-methylbenzylamine is 0.8eq, and the corresponding initial input amount of N-methylbenzylamine is 12.78g. For detailed data, see Table 1 below. In addition, the other reaction conditions are the same as those of Examples 1-4, and the reaction solution 14 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0109] Comparative Example 2

[0110] The difference between Comparative Example 2 and Examples 5-7 is that in the initial feeding of N-methylbenzylamine and anhydrous formic acid, the initial input amount of anhydrous formic acid is different based on the molar amount of naltrexone, and the initial input amount of anhydrous formic acid is <1.5eq. In Comparative Example 2, the initial input amount of anhydrous formic acid is 1.1eq, and the corresponding initial input amount of anhydrous formic acid is 6.67g. For detailed data, see Table 1 below. In addition, the other reaction conditions are the same as those of Examples 5-7, and the reaction solution 15 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0111] Comparative Example 3

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

[0113] Comparative Example 4

[0114] The difference between Comparative Example 4 and Examples 11-13 is that, in the additional 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, and the amount of anhydrous formic acid added each time is <0.2eq. In Comparative Example 4, the amount of anhydrous formic acid added each time is 0.1eq, and the corresponding amount of anhydrous formic acid added each time is 0.61g. For detailed data, see Table 1 below. In addition, the other reaction conditions are the same as those of Examples 11-13, and the reaction solution 17 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0115] Comparative Example 5

[0116] In Comparative Example 5, based on the molar amount of naltrexone, the initial charge of N-methylbenzylamine and anhydrous formic acid, the initial charge of N-methylbenzylamine <1eq, the initial charge of anhydrous formic acid ≥1.5eq; the additional charge of N-methylbenzylamine and anhydrous formic acid, the additional charge of N-methylbenzylamine each time ≥0.2eq, the additional charge of anhydrous formic acid each time ≥0.2eq; for detailed data, see Table 1 below, except for this, the other reaction conditions are the same as those in Example 1, and the reaction solution 18 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained in the corresponding step 1).

[0117] Comparative Example 6

[0118] In Comparative Example 6, based on the molar amount of naltrexone, the initial charge of N-methylbenzylamine and anhydrous formic acid, the initial charge of N-methylbenzylamine <1eq, the initial charge of anhydrous formic acid ≥1.5eq; the additional charge of N-methylbenzylamine and anhydrous formic acid, the additional charge of N-methylbenzylamine each time <0.2eq, the additional charge of anhydrous formic acid each time ≥0.2eq; for detailed data, see Table 1 below, except for this, the other reaction conditions are the same as those in Example 1, and the reaction solution 19 containing the nalfafen hydrochloride intermediate shown in Formula III is 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, and Example 1 is added multiple times. For detailed data, see Table 1 below. Apart from this, the other reaction conditions are the same as those in Example 1. In the corresponding step 1), the reaction solution 20 containing the nalfafen hydrochloride intermediate shown in Formula III is obtained.

[0121] Comparative Example 8

[0122] Referring to the "Improved Synthesis Process of Nalfurafen Hydrochloride" published by Lunan Pharmaceutical Group Co., Ltd., Shandong New Era Pharmaceutical Co., Ltd., and National Chiral Pharmaceutical Engineering Technology Research Center in the Chinese Journal of Medicinal Chemistry, a preparation method for the compound represented by formula III was prepared. The method prepared a reaction solution 21 containing the nalfurafen hydrochloride intermediate represented by formula III.

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

[0124] Table 1 Key materials and reaction conditions for the production of the intermediate nalfarapine hydrochloride shown in formula III

[0125]

[0126]

[0127] According to the detection method described in Example 1, the contents of naltrexone and the nalfarapine hydrochloride intermediate represented by Formula III in the reaction solution 1-21 were detected. The detection results and the conversion rate and effective conversion rate of the raw material naltrexone under various reaction conditions are shown in Table 2.

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

[0129]

[0130]

[0131] By observing Table 2, we can draw the following conclusions:

[0132] Comparing reaction solutions 1-4 and 14, it can be seen that the conversion rates of raw material naltrexone in Examples 1-4 all reached more than 90%, while the conversion rate of raw material naltrexone in Comparative Example 1 was less than 90%; and the effective conversion rate of raw material naltrexone in Examples 1-4 was also much higher than that in Comparative Example 1. Therefore, under the premise that other conditions were the same, changing the initial feed amount of N-methylbenzylamine significantly affected the conversion rate and effective conversion rate of raw material 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 solution 1 with reaction solutions 5-7 and 15, it can be seen that the conversion rates of raw material naltrexone in Examples 1 and 5-7 are all above 90%, while the conversion rate of raw material naltrexone in Comparative Example 2 is only 80.52%; and the effective conversion rate of raw material naltrexone in Examples 1 and 5-7 is also much higher than that in Comparative Example 2. Therefore, under the premise that other conditions are the same, changing the initial feed amount of anhydrous formic acid significantly affects the conversion rate and effective conversion rate of raw material naltrexone. When the initial feed amount of anhydrous formic acid is greater than or equal to 1.5 eq, the conversion rate and effective conversion rate of naltrexone are higher.

[0134] Comparing reaction solution 1 with reaction solutions 8-10 and reaction solution 16, it can be seen that the conversion rates of raw material naltrexone in Examples 1 and 8-10 are all above 90%, while the conversion rate of raw material naltrexone in Comparative Example 3 is less than 90%; and the effective conversion rate of raw material naltrexone in Examples 1 and 8-10 is also much higher than that in Comparative Example 3. Therefore, under the premise that other conditions are the same, changing the additional amount of N-methylbenzylamine significantly affects the conversion rate and effective conversion rate of raw material naltrexone. When the additional amount of N-methylbenzylamine is greater than or equal to 0.2 eq, the conversion rate and effective conversion rate of naltrexone are higher.

[0135] Comparing reaction solution 1 with reaction solutions 11-13 and reaction solution 17, it can be seen that the conversion rates of raw material naltrexone in Examples 1 and 11-13 all reached more than 90%, while the conversion rate of raw material naltrexone in Comparative Example 4 was less than 90%; and the effective conversion rate of raw material naltrexone in Examples 1 and 11-13 was also much higher than that in Comparative Example 4. Therefore, under the premise that other conditions were the same, changing the additional amount of anhydrous formic acid significantly affected the conversion rate and effective conversion rate of raw material naltrexone. When the additional amount of anhydrous formic acid was greater than or equal to 0.2 eq, the conversion rate and effective conversion rate of naltrexone were higher.

[0136] Comparing reaction solutions 1-13 with reaction solutions 18, 19, and 20, it can be seen that the conversion rates of raw material naltrexone in Examples 1-13 all reached more than 90%, while the conversion rates of raw material naltrexone in Comparative Examples 5, 6, and 7 were less than 90%; and the effective conversion rate of raw material naltrexone in Examples 1-13 was also much higher than that in Comparative Examples 5, 6, and 7. Therefore, under the premise that other conditions are the same, N-methylbenzylamine and anhydrous formic acid are added multiple times, and the initial input amount of N-methylbenzylamine is ≥1eq, and the initial input amount of anhydrous formic acid is ≥1.5eq; the additional input amount of N-methylbenzylamine is ≥0.2eq, and the additional input amount of anhydrous formic acid is ≥0.2eq, the conversion rate and effective conversion rate of naltrexone are higher.

[0137] Comparing reaction solutions 1-13 and reaction solution 21, it can be seen that the effective conversion rates of raw material naltrexone in Examples 1-13 are all over 80%, while the effective conversion rate of raw material 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 raw material naltrexone.

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

Claims

1. A method for preparing a nalfarapine hydrochloride intermediate, characterized in that: include: N-methylbenzylamine and anhydrous formic acid are added to naltrexone of formula Ⅰ for multiple times to carry out reductive amination reaction to obtain the nalfafen hydrochloride intermediate of formula Ⅲ. The synthetic route is as follows: 。 2. The method for preparing the nalfarapine hydrochloride intermediate according to claim 1, characterized in that: Based on the molar amount of naltrexone, the initial input amount of the N-methylbenzylamine is ≥1eq, and the initial input amount of the anhydrous formic acid is ≥1.5eq; the initial input amounts of the N-methylbenzylamine and the anhydrous formic acid are preferably 1.5eq:2eq.

3. The method for preparing the nalfarapine hydrochloride intermediate according to claim 1, characterized in that: The N-methylbenzylamine and the anhydrous formic acid are added 2-5 times, preferably 3-4 times.

4. The method for preparing the nalfarapine hydrochloride intermediate according to claim 1, characterized in that: Based on the molar amount of naltrexone, the additional amount of N-methylbenzylamine is ≥0.2eq, and the additional amount of anhydrous formic acid is ≥0.2eq.

5. The method for preparing the nalfarapine hydrochloride intermediate according to claim 1, characterized in that: The ratio of the additional amount of the N-methylbenzylamine to the anhydrous formic acid is (0.2-0.8eq):(0.2-0.8eq), preferably 0.5eq:0.5eq.

6. The method for preparing the nalfarapine hydrochloride intermediate according to claim 1, wherein: The solvent used in the reductive amination reaction can be any one of toluene, xylene, and ethylbenzene, or a combination of multiple thereof, preferably ethylbenzene; when ethylbenzene is selected as the solvent, the reaction temperature is 135-140°C.

7. A nalfarapine hydrochloride intermediate, characterized in that: The invention is obtained by using the preparation method described in any one of claims 1 to 6.

8. A method for preparing nalfarapine hydrochloride, characterized in that: The method uses the nalfarapine hydrochloride intermediate described in claim 7 as a raw material.

9. The method for preparing nalfarapine hydrochloride according to claim 8, characterized in that: The method comprises the following steps: a. Acid chloride reaction: The compound represented by the following formula IV is chlorinated in oxalyl chloride to obtain the compound represented by the following formula V, b. Hydrogenation debenzylation reaction: The intermediate of nalfarapine hydrochloride shown in the following formula III is hydrogenated and debenzylated in glacial acetic acid under the catalysis of palladium on carbon to obtain the compound shown in the following formula VI, c. Condensation reaction: Condensing the compound represented by the following formula V and the following formula VI, and treating to obtain nalfarapine hydrochloride free base, d. Salt formation: dissolving the free base of nalfarapine hydrochloride in methanol, adding hydrochloric acid to form a salt, and then adding isopropanol to crystallize to obtain the A-type nalfarapine hydrochloride. e. Crystal conversion: Dissolve the A-type nalfarapine hydrochloride in methanol, filter, concentrate the filtrate and slurry it with isopropanol. Amorphous nalfarapine hydrochloride is obtained. The synthetic route is as follows: 。 10. Nalfarafen hydrochloride, which is prepared according to the preparation method of claim 8 or 9.

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