A process for the preparation of nafagolide

Abstract

The application belongs to the technical field of medicine synthesis, and provides a preparation method of nalfurafine. 6beta-N-methyl-narceine and 3-furan propenoic acid are used as raw materials, Boc2O and DMAP are used as a catalytic system, a basic reagent is added, and temperature is controlled to perform reaction. The application has the characteristics of simple operation, mild reaction condition, fast reaction rate and the like, and the yield and purity of the product obtained by the application 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 nafpramine. Background Technology

[0002] Nalfurafine hydrochloride is a K-opioid receptor agonist that can be administered orally or intravenously to treat pruritus in patients with chronic kidney disease (CKD). Studies have shown that nalfurafine significantly reduces pruritus symptoms and has low psychological or physical dependence. The most common adverse reactions are insomnia and constipation. Nalfurafine (CAS: 152657-84-6), as a prodrug of nalfurafine hydrochloride, has the following chemical structure:

[0003]

[0004] Currently, there are many reported synthetic routes for nafuraphene-like compounds. For example, in CN1111900A, CN102325775A, and US2014031543A1, 3-furanylacrylic acid is prepared from oxaloyl chloride to 3-furanylacryloyl chloride, which is then reacted with 6α-N-methyl-(+)-naltrexamine to obtain (+)-nafuraphene. The same reaction type is also used in the literature Chem. Pharm. Bull. 46(2) 366-369 (1998). In CN104119348A, 3-furanylacryloyl chloride is prepared from formyl chloride and then reacted to obtain 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furanyl)acrylamido]morphinan. JP2015166331A discloses a method for reacting 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl)morphinan phthalate with 3-furanylacryloyl chloride in the presence of sodium carbonate to generate 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furanyl)acrylamido]morphinan, with an HPLC purity of 71.07%. The relevant route is as follows:

[0005]

[0006] In WO2010006119A1, 6β-N-methyl-naltrexamine and 3-furanylacrylic acid were used as raw materials to react under the action of BOP and DIEA to obtain 7-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furanyl)acrylamido]morphinan, with a yield of 95%. However, the product purity was poor. The relevant route is as follows:

[0007]

[0008] In addition, some new catalysts were selected for the synthesis of nafraprine analogs, using 3-furanylacrylic acid as a raw material, such as the catalyst used in WO2016152953A1: The synthetic route is as follows:

[0009]

[0010] It is evident that current methods for synthesizing nafpramine suffer from problems such as low product purity and unstable yield. Summary of the Invention

[0011] To address the problems existing in current nafrapine preparation technologies, this invention provides a novel method for preparing nafrapine. The target product obtained by this method has high purity and yield, and the production cost is low.

[0012] The technical solution of the present invention is as follows:

[0013] A method for preparing nafraprine involves using 6β-N-methyl-naltrexamine and 3-furanacrylic acid as raw materials under inert gas protection, with Boc₂O and DMAP as the catalytic system, adding a basic reagent, and carrying out the reaction at a controlled temperature. After post-treatment, nafraprine is obtained. The route is as follows:

[0014]

[0015] The reaction solvent is one of dichloromethane, acetonitrile, and toluene, preferably acetonitrile.

[0016] The molar ratio of 6β-N-methyl-naltrexamine to 3-furanacrylic acid is 1:1 to 1:2.0, preferably 1:1.4.

[0017] The molar ratio of 6β-N-methyl-naltrexamine to Boc2O is 1:1 to 1:2.0, preferably 1:1.5.

[0018] The molar ratio of 6β-N-methyl-naltrexamide to DMAP is 1:0.03 to 1:0.1, preferably 1:0.05.

[0019] The base is one of K2CO3, triethylamine, and 2,6-dimethylpyridine, preferably 2,6-dimethylpyridine.

[0020] The molar ratio of 6β-N-methyl-naltrexamine to the base is 1:0.06 to 1:0.15, preferably 1:0.1.

[0021] The temperature-controlled reaction is 20–35°C.

[0022] The reaction time is 3 to 10 hours.

[0023] The post-processing steps are as follows: after the reaction is detected to be complete, water and extraction solvent are added for extraction, the organic phase is concentrated to dryness to obtain an oily substance, and then pulped with solvent to obtain nafpramine.

[0024] The extraction solvent is one of dichloromethane, ethyl acetate, and toluene, preferably dichloromethane.

[0025] The pulping solvent is one of methanol, isopropanol, and ethanol, preferably methanol.

[0026] The inert gas is either nitrogen or argon.

[0027] Technical effects of the present invention:

[0028] This invention provides a novel method for preparing nafpramine, which is simple and easy to implement; it avoids the generation of byproducts, and the yield and purity of the obtained product are high, making it easy for industrial production. Attached Figure Description

[0029] Figure 1 This is the HPLC purity chromatogram of sodium furaprine from Example 1;

[0030] Figure 2 This is the HPLC purity chromatogram of sodium furaprine in Example 11;

[0031] Figure 3 This is the HPLC purity chromatogram of sodium furaprine in Comparative Example 1. Detailed Implementation

[0032] 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.

[0033] HPLC chromatographic conditions:

[0034] Column: Cyano-bonded silica gel as packing material (XDB-CN column)

[0035] Mobile phase A: 0.02 mol / L potassium dihydrogen phosphate (adjusted to pH 4.0 with phosphoric acid)

[0036] Mobile phase B: Acetonitrile

[0037] Column temperature: 40℃

[0038] Detector: UV at 215nm

[0039] Flow rate: 1.0 ml / min

[0040] Injection volume: 20ul

[0041] Analysis time: 60 min

[0042] HPLC gradient

[0043] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 45 55 45 47 95 5 60 95 5

[0044] Nafpramine identification data:

[0045] 1 HNMR(CDCl3)δ7.53(m,1H),7.46(d,J=15.2Hz,1H),7.40(m,1H),6.81(d,J=8.1Hz,1H),6.61(d,J=8.1Hz,1H),6.62(m,1H),6.34(d,J= 15.2Hz,1H),4.56(d,J=7.8Hz,1H),3.75(m,1H),3.11(m,2H),3.22(s,3H),2.79-1.40(m,11H),0.88(m,IH),0.52(m,2H),0.14(m,2H).

[0046] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0047] Example 1

[0048] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.960% and a yield of 96.2%.

[0049] Example 2

[0050] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.51 g, 4.2 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.803% and a yield of 94.5%.

[0051] Example 3

[0052] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (1.71 g, 14.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 4 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.841% and a yield of 94.9%.

[0053] Example 4

[0054] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (2.25 g, 21.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.856% and a yield of 95.4%.

[0055] Example 5

[0056] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (0.90 g, 8.40 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 8 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.781% and a yield of 94.3%.

[0057] Example 6

[0058] Under nitrogen atmosphere, 180 mL of dichloromethane, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 20 °C and stirred for 10 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.795% and a yield of 93.2%.

[0059] Example 7

[0060] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (19.34 g, 0.14 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and K₂CO₃ (1.93 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.820% and a yield of 93.9%.

[0061] Example 8

[0062] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (38.67 g, 0.28 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.843% and a yield of 94.6%.

[0063] Example 9

[0064] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and triethylamine (1.42 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of toluene were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of ethanol was added and the mixture was stirred for 1 hour. The mixture was filtered to obtain solid nalfurazone, with an HPLC purity of 99.784% and a yield of 94.5%.

[0065] Example 10

[0066] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (61.11 g, 0.28 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of isopropanol was added and the mixture was stirred for 1 hour. The mixture was then filtered to obtain solid nalfurazone, with an HPLC purity of 99.894% and a yield of 95.7%.

[0067] Example 11

[0068] Under nitrogen protection, 180 mL of acetonitrile, Boc₂O (30.56 g, 0.14 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 28 °C and stirred for 6 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of dichloromethane were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The product was filtered to obtain solid nalfurazone, with an HPLC purity of 99.806% and a yield of 93.1%.

[0069] Example 12

[0070] Under nitrogen atmosphere, 180 mL of toluene, Boc₂O (45.83 g, 0.21 mol), 3-furanacrylic acid (27.62 g, 0.20 mol), 6β-N-methyl-naltrexamine (50.00 g, 0.14 mol), DMAP (0.86 g, 7.00 mmol), and 2,6-dimethylpyridine (1.50 g, 14.00 mmol) were added to a three-necked flask. The mixture was heated to 35 °C and stirred for 4 hours. After the reaction was confirmed to be complete, 750 mL of water and 500 mL of ethyl acetate were added, and the mixture was stirred. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Then, 150 mL of methanol was added and the mixture was stirred for 1 hour. The mixture was filtered to obtain solid nalfurazone with a purity of 99.714% and a yield of 94.8%.

[0071] Comparative Example 1

[0072] 6-β-N-methylnaltrexamine (26.00 g, 0.07 mol) and 3-(3-furanyl)acrylic acid (15 g, 0.11 mol) were dissolved in anhydrous dichloromethane, followed by the addition of BOP (48.00 g, 0.11 mol) and N,N-diisopropylethylamine (0.04 L, 0.22 mol). The mixture was stirred for 2 hours, and then concentrated to dryness to obtain a crude product. This crude product was dissolved in MeOH (3 L), and then K₂CO₃ (300.00 g) was added. The mixture was stirred overnight at room temperature. The salts were filtered off, and the solvent was evaporated to dryness. The residue was purified by SiO₂ chromatography (CH₂Cl₂ / MeOH, 20:1, v:v). The target product, nalfuraphene, had an HPLC purity of 94.795% and a yield of 85.2%.

Claims

1. A process for the preparation of nafurafe, characterized in that, Narufline is prepared by using 6β-N-methyl-narceine and 3-furan acrylic acid as raw materials, Boc2O and DMAP as catalytic system, adding basic reagent, controlling temperature to react under inert gas protection, and treating after reaction; the route is as follows: ； The reaction solvent is one of dichloromethane, acetonitrile and toluene; The molar ratio of 6β-N-methyl-narceine, Boc2O and DMAP is 1:1-2.0:0.03-0.1; The base is one of K2CO3, triethylamine and 2,6-dimethylpyridine; The temperature of the controlled reaction is 20-35℃; The treating after reaction is that after detecting the reaction is completed, water and extraction solvent are added to extract, the organic phase is concentrated to dryness to obtain oil, and then the oil is beaten with a solvent to obtain narufline; The extraction solvent is one of dichloromethane, ethyl acetate and toluene; The beating solvent is one of methanol, isopropyl alcohol and ethanol.

2. The production method according to claim 1, wherein The molar ratio of 6β-N-methyl-narceine and 3-furan acrylic acid is 1:1-1:2.

0.

3. The production method according to claim 1, wherein The molar ratio of 6β-N-methyl-narceine and base is 1:0.06-1:0.15.

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