Preparation method of samidoprofen intermediate 3-formamide naltrexone

Abstract

The invention belongs to the technical field of medical intermediates, and provides a preparation method of a samidoprofen intermediate 3-formamide naltrexone. The preparation method comprises the following steps: mixing naltrexone, ethylene glycol, p-toluenesulfonic acid and toluene, and carrying out a reflux reaction to obtain a compound A; mixing the compound A, organic alkali and dichloromethane to obtain a mixed solution, dropwise adding trifluoromethanesulfonic anhydride into the mixed solution, and reacting to obtain a compound B; mixing the compound B, amine and N, N-dimethylformamide, and introducing carbon monoxide for reaction under the condition of a palladium catalyst to obtain a compound C; and adding the compound C into acid for hydrolysis reaction. According to the preparation method, highly toxic zinc cyanide does not need to be used, carbon monoxide is adopted as a carbonyl donor, and raw materials are easy to obtain; the reaction pressure is 0.1-0.5 MPa, the reaction conditions are mild, and industrial production is facilitated; the total molar yield of the 1, 3-formamide naltrexone reaches 71% or above, and the purity reaches 98.0% or above.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, and more particularly to a method for preparing the samidophen intermediate 3-formamide naltrexone. Background Technology

[0002] Samidorphan, a novel chemical substance with a structure similar to naltrexone, binds with high affinity to μ-opioid, κ-opioid, and δ-opioid receptors, acting as a μ-opioid receptor antagonist while also exhibiting partial agonistic activity against κ-opioid and δ-opioid receptors. In June 2021, the U.S. Food and Drug Administration (FDA) approved LYBALVI® (olanzapine samidophen tablets) for the treatment of schizophrenia and bipolar I disorder in adults, as a maintenance monotherapy or as adjunctive therapy to lithium or valproate for the acute treatment of manic or mixed episodes. The preparation method of 3-formamide naltrexone, a key intermediate in samidophen, is particularly important.

[0003] US0197905A1 discloses a method for preparing 3-carboxamide naltrexone. Using naltrexone as the starting material, the 3-hydroxyl group is first protected with trifluoromethanesulfonic anhydride, followed by a substitution reaction with tetra(triphenylphosphine)palladium and zinc cyanide to obtain a cyano intermediate. The cyano intermediate is then hydrolyzed to obtain 3-carboxamide naltrexone. This route requires the use of highly toxic zinc cyanide, posing a high production risk and hindering industrial-scale production. US10005790B2 discloses another method for preparing 3-carboxamide naltrexone. Using naltrexone as the starting material, the carbonyl group is first protected with an acetal, followed by activation of the 3-hydroxyl group with trifluoromethanesulfonic anhydride. Then, under the catalysis of palladium acetate and 1,1'-bis(diphenylphosphine)ferrocene, a substitution reaction is carried out with zinc cyanide in DMF, followed by hydrolysis and deprotection to obtain 3-carboxamide naltrexone. This route prolongs the reaction process and also uses the highly toxic zinc cyanide, making it unsuitable for industrial production.

[0004] CN118027047A discloses a method for preparing 3-formamide naltrexone to avoid the use of zinc cyanide. Using naltrexone as the starting material, the 3-hydroxyl group is protected with trifluoromethanesulfonic anhydride or N-phenylbis(trifluoromethanesulfonyl)imide. Then, the intermediate is mixed with a palladium catalyst, an organophosphorus ligand, a base, and an amine in a reaction solvent, and subjected to a high-pressure reaction at 20 bar using carbon monoxide to obtain 3-formamide naltrexone. While this method shortens the reaction route and avoids the use of zinc cyanide, the reaction process requires a pressure of 20 bar, placing high demands on equipment, resulting in high production costs and safety hazards. Furthermore, the yield of this method is only 56%, which is low. CN118598813A discloses a method for preparing 3-formamide naltrexone. Using naltrexone as a starting material, N,N-dimethylformamide reacts with a hydroxyl group at the 3-position to generate an amine ester intermediate. The amine ester intermediate then reacts with morpholinoacetonitrile under catalytic and ligand conditions to generate a cyano intermediate. The cyano intermediate is then hydrolyzed to obtain 3-formamide naltrexone. This route achieves a yield of 70%, but it uses a copper salt catalyst and a nickel catalyst system, requiring a relatively large amount of catalyst (0.05~0.2 equivalents), which increases production costs and is not conducive to industrial-scale production.

[0005] Therefore, it is essential to develop a highly efficient, low-toxicity, and economical method for preparing 3-formamide naltrexone that can avoid the use of the highly toxic reagent zinc cyanide and reduce safety risks. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing the samidophen intermediate 3-formamide naltrexone, addressing the shortcomings of existing technologies.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing the samidophen intermediate 3-formamide naltrexone, comprising the following steps: 1) Naltrexone, ethylene glycol, p-toluenesulfonic acid and toluene were mixed and refluxed to give compound A; 2) Compound A, an organic base, and dichloromethane were mixed to obtain a mixture. Trifluoromethanesulfonic anhydride was added dropwise to the mixture to carry out the reaction and obtain compound B. 3) Compound B, amine, and N,N-dimethylformamide were mixed and reacted with carbon monoxide under palladium catalyst conditions to obtain compound C; 4) Compound C is added to acid for hydrolysis to obtain 3-formamide naltrexone.

[0008] Preferably, the molar ratio of naltrexone, ethylene glycol and p-toluenesulfonic acid in step 1) is 1:2.5~5:1.2~5.

[0009] Preferably, the temperature of the reflux reaction in step 1) is 95~110℃.

[0010] Preferably, the organic base in step 2) is triethylamine, N,N-diisopropylethylamine, or pyridine.

[0011] Preferably, the molar ratio of compound A, organic base and trifluoromethanesulfonic anhydride in step 2) is 1:1.5~2:1.2~1.5; Step 2) The reaction temperature is -10~5℃, and the dropping rate is 9.0~15.0mL / min.

[0012] Preferably, the amine in step 3) is hexamethyldisilazane, hexaethyldisilazane, hexaphenyldisilazane, or tetramethyldiphenyldisilazane, and the palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, or palladium acetate.

[0013] Preferably, the molar ratio of compound B, amine, and palladium catalyst in step 3) is 1:2~8:0.007~0.01; Step 3) The reaction temperature is 80~100℃ and the reaction pressure is 0.1~0.5MPa.

[0014] Preferably, the acid in step 4) is hydrochloric acid, formic acid, phosphoric acid, or sulfuric acid, and the concentration of the acid is 2~5 mol / L.

[0015] Preferably, in step 4), the ratio of compound C to acid is 1 kg: 7~10 L, and the temperature of the hydrolysis reaction is 40~60℃.

[0016] The beneficial effects of this invention are: The preparation method of this invention does not require the use of highly toxic zinc cyanide, and uses carbon monoxide as a carbonyl donor, making the raw materials readily available; the reaction pressure is 0.1~0.5 MPa, the reaction conditions are mild, which is conducive to industrial production; the total molar yield of 3-carboxamide naltrexone reaches more than 71%, and the purity reaches more than 98%. Detailed Implementation

[0017] This invention provides a method for preparing the samidophen intermediate 3-formamide naltrexone, comprising the following steps: 1) Naltrexone, ethylene glycol, p-toluenesulfonic acid and toluene were mixed and refluxed to give compound A; 2) Compound A, an organic base, and dichloromethane were mixed to obtain a mixture. Trifluoromethanesulfonic anhydride was added dropwise to the mixture to carry out the reaction and obtain compound B. 3) Compound B, amine, and N,N-dimethylformamide were mixed and reacted with carbon monoxide under palladium catalyst conditions to obtain compound C; 4) Compound C is added to acid for hydrolysis to obtain 3-formamide naltrexone.

[0018] In this invention, naltrexone is used as the starting material. Ethylene glycol is used to protect the carbonyl group at the 6-position of naltrexone to obtain compound A (ketal compound). Then, trifluoromethanesulfonic anhydride is used to activate the hydroxyl group at the 3-position of compound A to obtain compound B (trifluoromethanesulfonate compound). Using carbon monoxide as a carbonyl donor, compound B undergoes a carbonylation reaction under the action of amine and palladium catalysts to obtain compound C (amide compound). Compound C is then hydrolyzed to obtain 3-formamide naltrexone.

[0019] In this invention, the molar ratio of naltrexone, ethylene glycol and p-toluenesulfonic acid in step 1) is preferably 1:2.5~5:1.2~5, more preferably 1:3~4.5:1.8~4, and even more preferably 1:3.5~4:2~3.5.

[0020] In this invention, the temperature of the reflux reaction in step 1) is preferably 95~110℃, and more preferably 100~105℃.

[0021] In this invention, the reflux reaction in step 1) is preferably controlled by HPLC to the reaction endpoint.

[0022] In this invention, the preferred ratio of naltrexone to toluene in step 1) is 1 kg: 3~10 L, and more preferably 1 kg: 5~6 L.

[0023] In this invention, after the reflux reaction in step 1) is completed, it is preferable to add purified water to the reaction solution, stir and separate the liquid, retain the aqueous phase, crystallize and filter the aqueous phase to obtain compound A; The pH value for crystallization is preferably 8.5 to 9.5, and more preferably 9.0.

[0024] In this invention, the organic base in step 2) is preferably triethylamine, N,N-diisopropylethylamine, or pyridine.

[0025] In this invention, the molar ratio of compound A, organic base and trifluoromethanesulfonic anhydride in step 2) is preferably 1:1.5~2:1.2~1.5, more preferably 1:1.6~1.9:1.25~1.45, and even more preferably 1:1.7~1.8:1.3~1.4; The reaction temperature in step 2) is preferably -10~5℃, more preferably -8~2℃, and even more preferably -5~0℃; the dropping rate is preferably 9.0~15.0mL / min, more preferably 9.5~12.0mL / min, and even more preferably 10.0~11.0mL / min.

[0026] In this invention, the reaction described in step 2) is preferably controlled to the reaction endpoint by HPLC.

[0027] In this invention, the preferred ratio of compound A to dichloromethane in step 2) is 1 kg: 1~5 L, and more preferably 1 kg: 3~4 L.

[0028] In this invention, after the reaction described in step 2) is completed, the reaction is preferably quenched, followed by washing the organic phase and drying to obtain compound B; The organic phase is washed sequentially with a saturated ammonium chloride aqueous solution, water, and a saturated sodium chloride aqueous solution.

[0029] In this invention, the amine in step 3) is preferably hexamethyldisilazane, hexaethyldisilazane, hexaphenyldisilazane, or tetramethyldiphenyldisilazane, and the palladium catalyst is preferably 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, or palladium acetate.

[0030] In this invention, the molar ratio of compound B, amine and palladium catalyst in step 3) is preferably 1:2~8:0.007~0.01, more preferably 1:3~6:0.008~0.009, and even more preferably 1:4~5:0.0085; The reaction temperature in step 3) is preferably 80~100℃, more preferably 85~95℃, and even more preferably 90℃; the reaction pressure is preferably 0.1~0.5MPa, more preferably 0.2~0.4MPa, and even more preferably 0.3MPa.

[0031] In this invention, the reaction described in step 3) is preferably controlled to the reaction endpoint by HPLC.

[0032] In this invention, the mass ratio of compound B and N,N-dimethylformamide in step 3) is preferably 1:3~6, and more preferably 1:4~5.

[0033] In this invention, after the reaction in step 3) is completed, it is preferable to first concentrate the reaction solution, then add acid to dissolve it, and then perform crystallization and filtration to obtain a crude product; the crude product is dissolved in a recrystallization solvent and filtered, and the filtrate is subjected to low-temperature crystallization to obtain compound C; The pH value for crystallization is preferably 10.5 to 11.5, more preferably 11; The preferred temperature for low-temperature crystallization is 5~10℃, more preferably 6~8℃; the preferred time for low-temperature crystallization is 6~8h, more preferably 7h. The acid solution preferably contains formic acid, acetic acid, sulfuric acid, or phosphoric acid; The preferred recrystallization solvent is ethyl acetate, 2-methyltetrahydrofuran, or anhydrous ethanol.

[0034] In this invention, the acid in step 4) is preferably hydrochloric acid, formic acid, phosphoric acid or sulfuric acid, and the concentration of the acid is preferably 2~5 mol / L, more preferably 3~4 mol / L, and even more preferably 3.5 mol / L.

[0035] In this invention, the preferred ratio of compound C to acid in step 4) is 1 kg: 7~10 L, more preferably 1 kg: 7.5~9 L, and even more preferably 1 kg: 8~8.5 L; the preferred temperature of the hydrolysis reaction is 40~60℃, more preferably 45~55℃, and even more preferably 50℃.

[0036] In this invention, the hydrolysis reaction in step 4) is preferably controlled by HPLC to the reaction endpoint.

[0037] In this invention, after the hydrolysis reaction in step 4) is completed, it is preferable to first extract the aqueous phase, and then crystallize and filter the aqueous phase to obtain 3-formamide naltrexone. The preferred extractant used in the extraction is toluene and / or dichloromethane; The pH value for crystallization is preferably 8.5 to 9.5, more preferably 9; the crystallization temperature is preferably 0 to 10°C, more preferably 5°C.

[0038] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0039] Example 1

[0040] 1989.5 g of naltrexone (5.83 mol) was added to a reaction vessel, followed by 12 L of toluene, 1737.84 g of ethylene glycol (28.00 mol), and 1204.20 g of p-toluenesulfonic acid (7 mol). The reaction vessel was heated to 100 °C and refluxed at 100 °C, with the reaction controlled by HPLC to the endpoint. The reaction vessel was then cooled to 60 °C, and 20 L of purified water was added. After stirring thoroughly, the mixture was allowed to stand and separated to obtain the aqueous phase. The pH of the aqueous phase was adjusted to 9.0 with ammonia, and crystals were precipitated at 15 °C for 3 h. The crystals were then filtered and dried at 80 °C for 10 h to obtain 2160.71 g of white solid, which was compound A. The molar yield of compound A in this step was 96.15%.

[0041] The chemical reaction that occurs in this step is: .

[0042] 2042.61 g of compound A (5.30 mol) was added to a reaction vessel, followed by 6.73 L of dichloromethane and 1026.50 g of N,N-diisopropylethylamine (7.96 mol). After cooling to 0 °C, 1794.0 g of trifluoromethanesulfonic anhydride (6.36 mol) was added dropwise at a rate of 10.92 mL / min. The reaction was maintained at 0 °C, and the reaction was monitored to the endpoint by HPLC. After the reaction was completed, the reaction was quenched to obtain the organic phase. The organic phase was then washed successively with 6 L of saturated ammonium chloride aqueous solution, 6 L of water, and 6 L of saturated sodium chloride aqueous solution. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure at 40 °C to obtain a viscous solid. Finally, the solid was dried at 80 °C for 12 h to obtain 2716.80 g of compound B. The molar yield of compound B in this step was 99.05%.

[0043] The chemical reaction that occurs in this step is: .

[0044] 2700.86 g of compound B (5.22 mol) was added to an autoclave, followed by 13.0 kg of N,N-dimethylformamide, 36.56 g of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloromethane complex (0.04 mol), and 2064.18 g of hexamethyldisilazane (12.79 mol). The air in the autoclave was purged with nitrogen three times, followed by three more purgings with carbon monoxide. After purging, carbon monoxide was introduced into the autoclave until the pressure reached 0.5 MPa. The reaction was carried out at 90°C and maintained under pressure, with HPLC monitoring until the reaction endpoint was reached. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 100℃ until viscous. Then, 20 L of 30% formic acid was added, and the mixture was stirred at 40℃ for 2 h to dissolve the concentrate. The solution was then cooled to 10℃, and the pH of the filtrate was adjusted to 11 with sodium hydroxide solution. Crystallization was carried out at 10℃ for 10 h, followed by filtration. The solid product was dried at 80℃ for 10 h to obtain a crude product (2635.57 g). The 2635.57 g crude product was added to a reaction vessel, and 35 L of ethyl acetate was added for reflux dissolution for 1 h. After filtration, the filtrate was concentrated under reduced pressure to half of the original volume. The solution was then cooled to 10℃ and crystallized at 10℃ for 6 h, followed by filtration. The solid product was dried at 80℃ for 5 h to obtain 1790.60 g of white solid, which is compound C. The molar yield of compound C in this step was 83.16%.

[0045] The structure of compound C was characterized, and the results are as follows: Mass spectrometry (MS-ES) (m / z): [M+H) + 413.09 Hydrogen spectrum: 1 H NMR (600 MHz, DMSO- d 6) δ 7.54 (d, J = 8.0 Hz, 1H), 7.47 (s,1H), 7.01 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 4.98 (s, 1H), 4.63 (s, 1H), 4.06(dd, J = 12.8, 6.3 Hz, 1H), 3.84 – 3.77 (m, 1H), 3.73 – 3.64 (m, 2H), 3.11 –3.02 (m, 2H), 2.61 (dd, J = 19.1, 5.6 Hz, 2H), 2.42 – 2.29 (m, 2H), 2.24 (td, J = 12.5, 5.1 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.90 (td, J = 12.2, 3.8 Hz, 1H),1.51 – 1.42 (m, 2H), 1.42 – 1.34 (m, 1H), 1.22 (dd, J = 12.8, 2.4 Hz, 1H), 0.84 (m, 1H), 0.47 (m, 2H), 0.12 (m, 2H). Carbon spectrum: 13 C NMR (151 MHz, DMSO) δ 165.04, 156.41, 136.97, 129.82, 128.45,118.18, 112.79, 108.22, 93.33, 69.15, 65.72, 64.22, 61.20, 58.20, 46.74,43.06, 30.69, 28.85, 28.28, 22.99, 9.18, 3.70, 3.53. The chemical reaction in this step is: .

[0046] 3571.4 g (8.66 mol) of compound C was added to a reaction vessel, followed by the addition of 25 L of 3.5 mol / L hydrochloric acid. The mixture was heated to 50 °C and subjected to hydrolysis at 50 °C, with the reaction time monitored by HPLC until the endpoint was reached. After hydrolysis, the reaction solution was extracted with 10 L of dichloromethane. The two extractions were combined, and the pH of the aqueous phase was adjusted to 8.0 with ammonia. Crystallization was then carried out at 5 °C for 6 h, followed by filtration. The solid product was dried at 80 °C for 10 h to obtain 2971.74 g of a white solid, which was 3-formamide naltrexone. The molar yield of 3-formamide naltrexone in this step was 93.14%.

[0047] The structure of 3-formamide naltrexone was characterized, and the results are as follows: Mass spectrometry (MS-ES) (m / z): [MH] - 367.16 Hydrogen spectrum: 1 H NMR (600 MHz, DMSO- d 6) δ 7.66 (s, 1H), 7.54 (d, J = 8.0Hz,1H), 7.10 (s, 1H), 6.85 (d, J = 8.0Hz, 1H), 5.16 (s, 2H), 3.19 (d, J = 5.7Hz, 1H), 3.11 (d, J = 19.3 Hz, 1H), 2.98 (td, J = 14.2, 5.0 Hz, 1H), 2.65(td, J = 19.4, 18.9, 9.0 Hz, 2H), 2.40 (dqd, J = 24.1, 12.6, 5.8 Hz, 3H),2.13 (dt, J = 13.8, 3.1 Hz, 1H), 1.92 (td, J = 12.2, 3.7 Hz, 1H), 1.87 – 1.75(m, 1H), 1.42 (td, J = 14.1, 3.3 Hz, 1H), 1.35 (d, J = 12.9 Hz, 1H), 0.89 (m,1H), 0.49 (m, 2H), 0.14 (m, 2H). Carbon spectrum: 13C NMR (151 MHz, DMSO) δ 207.93, 164.56, 154.83, 138.04, 128.82,128.76, 119.55, 114.44, 91.14, 69.62, 60.87, 58.30, 49.80, 42.94, 35.61,31.45, 29.84, 23.09, 9.13, 3.74, 3.56. The chemical reaction in this step is: .

[0048] In this example, the total molar yield of 3-formamide naltrexone was 73.77%, and the purity was 98.48%.

[0049] Example 2

[0050] The difference from Example 1 is that 10g of compound B (19.32mmol) was added to an autoclave, followed by 50g of N,N-dimethylformamide, 0.11g of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.15mmol), and 9.35g of hexamethyldisilazane (57.96mmol). The air in the autoclave was replaced with nitrogen three times, followed by three more replacements with carbon monoxide. After replacement, carbon monoxide was introduced into the autoclave to a pressure of 0.5MPa, and the reaction was carried out at 90°C under maintained pressure. The reaction was monitored by HPLC until the endpoint was reached. After the reaction, the reaction solution was concentrated to a viscous consistency, and then 10mL of 25% formic acid was added. The mixture was stirred at 40°C for 1 hour to dissolve the concentrate. The solution was then cooled to 10°C, and the pH of the filtrate was adjusted to 11 with sodium hydroxide solution. Crystallization was carried out at 10°C for 6 hours, followed by filtration. The solid product was dried at 80°C for 6 hours to obtain the crude product. The crude product was added to a reaction vessel, and 140 mL of ethyl acetate was added for reflux dissolution. The mixture was filtered, and the filtrate was concentrated to half its original volume. The solution was then cooled to 10°C and crystallized at 10°C for 6 hours. The crystals were then filtered, and the solid product was dried at 80°C for 4 hours to obtain 6.45 g of a white solid, which was compound C. The molar yield of compound C in this step was 80.92%.

[0051] In this example, the total molar yield of 3-formamide naltrexone was 71.78%, and the purity was 98.21%.

[0052] As shown in the above examples, this invention provides a method for preparing the samidophen intermediate 3-carboxamide naltrexone. Using naltrexone as a raw material, the 6-carbonyl group of naltrexone is protected in toluene with ethylene glycol to obtain a ketal intermediate (compound A). Then, the 3-hydroxyl group of compound A is activated with trifluoromethanesulfonic anhydride to obtain a trifluoromethanesulfonate intermediate (compound B). Subsequently, a carbonylation reaction is carried out in N,N-dimethylformamide using carbon monoxide as a carbonyl donor under the action of a palladium catalyst and an amine to obtain an amide intermediate (compound C). Compound C undergoes acid deprotection to obtain 3-carboxamide naltrexone. This route avoids the use of highly toxic zinc cyanide, uses carbon monoxide, an amine, and a palladium catalyst for the carbonylation reaction, and the raw materials are readily available. The reaction pressure is 0.1~0.5 MPa, the reaction conditions are mild, and the total molar yield of 3-carboxamide naltrexone reaches over 71%, with a purity of over 98%.

[0053] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing the samidophen intermediate 3-formamide naltrexone, characterized in that, It includes the following steps: 1) Naltrexone, ethylene glycol, p-toluenesulfonic acid and toluene were mixed and refluxed to give compound A; 2) Compound A, an organic base, and dichloromethane were mixed to obtain a mixture. Trifluoromethanesulfonic anhydride was added dropwise to the mixture to carry out the reaction and obtain compound B. 3) Compound B, amine, and N,N-dimethylformamide were mixed and reacted with carbon monoxide under palladium catalyst conditions to obtain compound C; 4) Compound C is added to acid for hydrolysis to obtain 3-formamide naltrexone.

2. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 1, characterized in that, In step 1), the molar ratio of naltrexone, ethylene glycol, and p-toluenesulfonic acid is 1:2.5~5:1.2~5.

3. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 1 or 2, characterized in that, The reflux reaction temperature in step 1) is 95~110℃.

4. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 3, characterized in that, The organic base in step 2) is triethylamine, N,N-diisopropylethylamine, or pyridine.

5. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 4, characterized in that, In step 2), the molar ratio of compound A, organic base, and trifluoromethanesulfonic anhydride is 1:1.5~2:1.2~1.

5. Step 2) The reaction temperature is -10~5℃, and the dropping rate is 9.0~15.0mL / min.

6. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 4 or 5, characterized in that, Step 3) The amine is hexamethyldisilazane, hexaethyldisilazane, hexaphenyldisilazane, or tetramethyldiphenyldisilazane, and the palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, or palladium acetate.

7. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 6, characterized in that, In step 3), the molar ratio of compound B, amine, and palladium catalyst is 1:2~8:0.007~0.

01. Step 3) The reaction temperature is 80~100℃ and the reaction pressure is 0.1~0.5MPa.

8. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 1 or 7, characterized in that, Step 4) The acid is hydrochloric acid, formic acid, phosphoric acid or sulfuric acid, and the concentration of the acid is 2~5 mol / L.

9. The method for preparing the samidophen intermediate 3-formamide naltrexone according to claim 8, characterized in that, Step 4) The ratio of compound C to acid is 1 kg: 7~10 L, and the temperature of the hydrolysis reaction is 40~60℃.