A process for the preparation of naltrexone

Abstract

The application belongs to the technical field of medicine synthesis, and provides a preparation method of naltrexone, wherein norethoxy-morphinone and cyclopropylmethanol are used as raw materials, and PdCl2 (Xantphos) is used as a catalyst to perform reaction. The application has the characteristics of simple operation, mild reaction condition and the like, and the yield and purity of the obtained product are high, and the application is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing naltrexone. Background Technology

[0002] Naltrexone is an opioid receptor antagonist primarily used to control alcohol and opioid dependence. Its primary use is in the treatment of alcohol dependence. It is generally marketed as its hydrochloride salt (naltrexone hydrochloride) under the brand names ReVia and Depade. In some countries, including the United States, a once-monthly extended-release injectable formulation is marketed under the brand name ViVitrol.

[0003] Naltrexone can be prepared from norhydroxymorphone via various direct and indirect alkylation methods. One method involves the direct alkylation of norhydroxymorphone with cyclopropylmethyl bromide compounds. This method has been disclosed in summary form in Rice WO91 / 05768. Sanofi-Avensisd WO2008 / 034973 (Chinese equivalent CN101516892A) describes a method for obtaining naltrexone in 88.6% yield by reacting norhydroxymorphone hydrochloride with cyclopropylmethyl bromide in dimethylacetamide in the presence of sodium bicarbonate. Cilag WO2008 / 138605 describes the N-alkylation reaction of norhydroxymorphone with cyclopropylmethyl bromide in N-methylpyrrolidone in the presence of sodium bicarbonate. Mallinckrodt's WO2010 / 039209 describes the N-alkylation of norhydroxymorphone with cyclopropylmethyl bromide in the presence of a proton solvent. The embodiment in WO2010 / 039209 (Chinese equivalent CN102227433A) describes the addition of water / isopropanol or ethanol as a proton solvent, generating not only the main product naltrexone, but also byproducts such as 3-cyclopropylmethylnaltrexone and quaternary ammonium salts. CN103237804A discloses the reaction of norhydroxymorphone with cyclopropylmethyl halides in the presence of N-ethyl-2-pyrrolidone. In Example 1, the composition of the reaction mixture (in percentage area) was determined by HPLC: naltrexone 97.3%, norhydroxymorphone 1.4%, 3-cyclopropylmethylnaltrexone 0.4%. WO2013 / 164383 and US2011269964A1 describe the synthesis of naltrexone from norhydroxymorphone and cyclopropylmethyl chloride in the presence of NaHCO3, NaBr, and Bu3NMeBr. The reaction route is as follows:

[0004]

[0005] CN101027307A describes the preparation of naltrexone or its hydrochloride salt from desmethylmorphorne and cyclopropaneformaldehyde under palladium or platinum catalysis (yield 83%). CN102227434A describes the preparation of naltrexone base from desmethylmorphorne and cyclopropaneformaldehyde by hydrogen transfer under the catalysis of triethylamine, formic acid, and the catalyst dichloro(p-methylisopropylbenzene)Ru(II) dimer (yield 95%). However, these methods suffer from problems such as long reaction time, numerous byproducts, incomplete reaction, and complex separation and purification procedures. US2015 / 126741A1 uses sodium triacetoxyborohydride as a catalyst to catalyze the synthesis of naltrexone from desmethylmorphorne and cyclopropaneformaldehyde. US2010 / 210843A1 and US2015 / 126741A1 also use desmethylmorphorne and cyclopropaneformaldehyde as raw materials. The reaction routes are as follows:

[0006]

[0007] CN102046631A describes the preparation of naltrexone (74% yield) using desmethylmorphorne and cyclopropane-methanol in the presence of methanesulfonyl chloride, triethylamine, lithium bromide, and other reagents. Sipos, Attila et al., First Synthesis and Utilization of Oripavidine-A Concise and Efficient Route to Important Morphinans and Apomorphines[J], Helvetica Chimica Acta, 92(7), 1359-1365; 2009, describes the preparation of naltrexone using desmethylmorphorne and cyclopropane-methanol as raw materials in a microwave reactor with dichloro(pentamethylcyclopentadienyl)iridium(III) dimer ([Cp*IrCl2]2) as a catalyst. The reaction route is as follows:

[0008]

[0009] Analysis of existing technologies reveals that norhydroxymorphone and its hydrochloride are the main raw materials for the synthesis of naltrexone. Naltrexone is obtained by reacting with cyclopropyl halogens, cyclopropyl formaldehyde, and cyclopropyl methanol. However, these methods have problems such as producing many byproducts, using complex catalysts, being difficult to operate, and being difficult to industrialize. Summary of the Invention

[0010] To address the problems existing in current naltrexone preparation technologies, this invention provides a novel method for preparing naltrexone. The target product obtained by this method has high purity and yield, and the production cost is low.

[0011] The technical solution of the present invention is as follows:

[0012] A method for preparing naltrexone involves reacting desmethylhydroxymorphone and cyclopropanol as raw materials under an inert gas atmosphere with 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (PdCl2(Xantphos)) as a catalyst, followed by post-treatment to obtain naltrexone. The route is as follows:

[0013]

[0014] Preferably, the preparation method includes the following steps:

[0015] Under inert gas protection, PdCl2 (Xantphos) and reaction solvent were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropane-methanol was added and stirred until homogeneous. Demethylhydroxymorphone was then added, and the reaction mixture was stirred under controlled temperature. Water and extraction solvent were added to the reaction flask for extraction. The organic phase was concentrated to dryness to obtain an oily substance, which was then slurried with solvent to obtain the product naltrexone.

[0016] Preferably, the reaction solvent is one of isopropanol, 1,4-dioxane, and methyl tert-butyl ether, and more preferably isopropanol.

[0017] Preferably, the molar ratio of norhydroxymorphone to cyclopropanol is 1:1 to 1:1.5, and more preferably 1:1.3.

[0018] Preferably, the molar ratio of norhydroxymorphone to PdCl2 (Xantphos) is 1:0.03 to 1:0.1, and more preferably 1:0.05.

[0019] Preferably, the temperature-controlled reaction is at 20–35°C.

[0020] Preferably, the reaction time is 5 to 10 hours.

[0021] Preferably, the extraction solvent is one of dichloromethane, ethyl acetate, and toluene, and more preferably dichloromethane.

[0022] Preferably, the pulping solvent is one of n-hexane, isopropyl ether, and petroleum ether, and more preferably n-hexane.

[0023] The inert gas is either nitrogen or argon.

[0024] Technical effects of the present invention:

[0025] This invention provides a novel method for preparing naltrexone, which is simple and easy to operate. Using PdCl2 (Xantphos) as a catalyst, it solves the problems of long reaction time and difficulty in separating and purifying many byproducts in the existing technology using dichloro(p-methylisopropylbenzene)Ru(II) dimer. Furthermore, the yield and purity of the obtained product are high, making it easy to carry out industrial production. Attached Figure Description

[0026] Figure 1 This is the HPLC chromatogram of naltrexone obtained in Example 1;

[0027] Figure 2 This is the HPLC chromatogram of naltrexone obtained in Example 2. Detailed Implementation

[0028] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0029] HPLC detection, chromatographic conditions as follows:

[0030] Column: Octadecyl silica bonded silica gel as filler (SB-C) 18 (l=0.15m, Φ=4.6mm, 5μm)

[0031] Mobile phase A: Aqueous phase (1.1 g / L sodium octane sulfonate, pH adjusted to 2.3 with phosphoric acid)

[0032] Mobile phase B: Acetonitrile

[0033] Column temperature: 40℃

[0034] Detector: UV at 230nm

[0035] Injection volume: 10 μl

[0036] Analysis time: 60 min

[0037] HPLC gradient

[0038] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 45 55 45 47 90 10 60 90 10

[0039] Identification data for naltrexone:

[0040] 1H NMR (600MHz, CDCl3) δ6.73(d,J=8.1Hz,1H),6.60(d,J=8.1Hz,1H),5.72(bs,1H,OH),4.76(s,1H),3.21 (d,J=5.9Hz,1H),3.11-3.03(m,2H),2.73(dd,J=12.0,4.8Hz,1H),2.56(dd,J=18.4,6.0Hz,1H),2.50- 2.34(m,3H),2.36(ddd,J=14.5,3.0,3.0Hz,1H),2.18(ddd,J=12.2,3.8,3.8Hz,1H),1.92(m,1H),1.66 (ddd,J=14.2,14.2,3.3Hz,1H),1.57(ddd,J=12.8,2.7Hz,1H),0.88(m,1H),0.56(m,2H),0.16(m,2H);

[0041] 13 C NMR (150MHz, CDCl3): d=209.90,142.51,138.90,129.05,124.04,119.77,117.91,90. 46,70.32,61.94,59.21,51.04,43.60,36.41,31.36,30.65,22.62,9.37,4.02,3.78.

[0042] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0043] Example 1

[0044] Under inert nitrogen protection, PdCl2 (Xantphos) (6.43 g, 8.50 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 8 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 96.5% and an HPLC purity of 99.834%.

[0045] Example 2

[0046] Under inert nitrogen protection, PdCl2 (Xantphos) (14.14 g, 18.70 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 5 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 95.5% and an HPLC purity of 99.801%.

[0047] Example 3

[0048] Under inert nitrogen protection, PdCl2 (Xantphos) (2.57 g, 3.40 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 10 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 93.4% and an HPLC purity of 99.753%.

[0049] Example 4

[0050] Under inert nitrogen protection, PdCl2 (Xantphos) (12.85 g, 17.00 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 6 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and the mixture was stirred for 1.5 h to obtain the product naltrexone, with a yield of 94.8% and an HPLC purity of 99.813%.

[0051] Example 5

[0052] Under inert nitrogen protection, PdCl2 (Xantphos) (12.85 g, 17.00 mmol) and 1,4-dioxane (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropane methanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 8 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of ethyl acetate were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 94.6% and an HPLC purity of 99.802%.

[0053] Example 6

[0054] Under inert nitrogen protection, PdCl2 (Xantphos) (3.86 g, 5.10 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 10 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 93.9% and an HPLC purity of 99.764%.

[0055] Example 7

[0056] Under inert nitrogen protection, PdCl2 (Xantphos) (6.43 g, 8.50 mmol) and 1,4-dioxane (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropane methanol (12.26 g, 0.17 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 8 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 94.4% and an HPLC purity of 99.803%.

[0057] Example 8

[0058] Under inert nitrogen protection, PdCl2 (Xantphos) (6.43 g, 8.50 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (18.75 g, 0.26 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 25 °C for 8 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of n-hexane was added and stirred for 1 h to obtain the product naltrexone, with a yield of 96.1% and an HPLC purity of 99.798%.

[0059] Example 9

[0060] Under inert nitrogen protection, PdCl2 (Xantphos) (6.43 g, 8.50 mmol) and methyl tert-butyl ether (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropane methanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, norhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 20 °C for 10 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of dichloromethane were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of isopropyl ether was added and the mixture was stirred for 1 h to obtain the product naltrexone, with a yield of 95.4% and an HPLC purity of 99.724%.

[0061] Example 10

[0062] Under inert nitrogen protection, PdCl2 (Xantphos) (6.43 g, 8.50 mmol) and isopropanol (60 mL) were added to a three-necked flask at room temperature and stirred until homogeneous. Then, cyclopropanol (15.86 g, 0.22 mol) was added and stirred until homogeneous. Next, demethylhydroxymorphone (50.00 g, 0.17 mol) was added. The reaction mixture was stirred at 35 °C for 6 h. After the reaction was confirmed to be complete, 100 mL of water and 100 mL of toluene were added to the reaction flask, stirred, separated, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain an oily substance. Then, 60 mL of petroleum ether was added and the mixture was stirred for 1 h to obtain the product naltrexone, with a yield of 95.9% and an HPLC purity of 99.730%.

Claims

1. A method for preparing naltrexone, characterized in that, Under inert gas protection and at room temperature, PdCl2 (Xantphos) and reaction solvent were added to a three-necked flask and stirred until homogeneous. Then, cyclopropane-methanol was added and stirred until homogeneous. Demethylhydroxymorphone was then added, and the reaction mixture was stirred under controlled temperature. When the reaction was completed, water and extraction solvent were added to the reaction flask for extraction. The organic phase was concentrated to dryness to obtain an oily substance, which was then slurried with solvent to obtain the product naltrexone. The molar ratio of norhydroxymorphone to PdCl2 (Xantphos) is 1:0.03 to 1:0.1; The temperature-controlled reaction is 20–35°C; The reaction solvent is one of isopropanol, 1,4-dioxane, or methyl tert-butyl ether; The route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of norhydroxymorphone to cyclopropanol is 1:1 to 1:1.

5.

3. The preparation method according to claim 1, characterized in that, The extraction solvent is one of dichloromethane, ethyl acetate, and toluene.

4. The preparation method according to claim 1, characterized in that, The pulping solvent is one of n-hexane, isopropyl ether, and petroleum ether.

5. The preparation method according to claim 1, characterized in that, The temperature-controlled reaction time is 5–10 hours.

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