A method for preparing an intermediate of nalfurafine

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis. The present invention provides a method for preparing the naloxone intermediate 6β-N-methyl-naltrexamine, which uses naltrexone and methylamine as raw materials and reacts under the action of a chiral phosphoric acid catalyst to obtain 6β-N-methyl-naltrexamine with a higher yield and chiral purity; the raw materials of the present invention are easily available, the reaction conditions are mild, etc., and the post-treatment is simple and more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing the nalfurafine intermediate 6β-N-methyl-naltrexamine. Background Art

[0002] Nalfurafine is a κ-opioid receptor agonist and can be administered orally or intravenously to treat pruritus in CKD patients. Nalfurafine can significantly reduce the pruritus symptoms of patients, has less psychological or physical dependence on the drug, and the most common adverse reactions are insomnia and constipation. The chemical structural formula of nalfurafine is as follows:

[0003]

[0004] Currently, there are many reported synthetic routes for nalfurafine analog compounds. For example, in Chinese patents CN1111900A, CN102325775A, CN104119348A, JP2015166331A, US2014031543A1 and the literature Chem. Pharm. Bull., 1998, 46(2): 366-369, 3-furanacrylic acid is first converted into 3-furylacryloyl chloride and then reacted with 6β-N-methyl-naltrexamine to obtain nalfurafine. The related routes are as follows:

[0005]

[0006] As can be seen from the above, 6β-N-methyl-(+)-naltrexamine, as a key intermediate for synthesizing nalfurafine hydrochloride, directly affects the production, market supply and quality of this drug. Its structural formula is as follows:

[0007]

[0008] Currently, the preparation methods of 6β-N-methyl-naltrexamine are described in the literature J. Med. Chem., 1986, 29, 8, 1551-1553; WO2020205735A1, US6277859B1, US5972953A, CN94190473. The preparation methods of 6β-N-methyl-naltrexamine mostly use naltrexone as the starting material, first undergo reductive amination reaction with N-methylbenzylamine, and then catalytic hydrogenolysis to remove the benzyl group. However, on the one hand, for constructing the 6β-N-methyl structure, benzyl protection is required to induce generation, which makes the subsequent deprotection require a relatively dangerous hydrogenation reaction. At the same time, N-methylbenzylamine is introduced by reductive amination reaction, and relatively dangerous borohydrides are used therein, making it difficult to achieve industrial scale-up production. The related routes are as follows:

[0009]

[0010] In Patent WO2010006119A1 and the literature J. Med. Chem., 1986, 29, 8, 1551 - 1553, naltrexone was used as a raw material to react with methylamine or methylamine hydrochloride under the action of NaBH3CN, and after purification by column chromatography, 6α - N - methyl - naltrexamine and 6β - N - methyl - naltrexamine (yield about 32%) were obtained. The related route is as follows:

[0011]

[0012] In summary, in view of the above deficiencies in the current preparation methods of 6β - N - methyl - naltrexamine, therefore, it is still a problem to be solved at present to study and find a reaction route suitable for industrial production of 6β - N - methyl - naltrexamine with a simple operation process, high product yield and high purity. Summary of the Invention

[0013] In view of the problems existing in the current preparation technology of 6β - N - methyl - naltrexamine, the present invention provides a new preparation method of 6β - N - methyl - naltrexamine. The target product obtained by this method has high purity and yield, and is suitable for industrial scale - up production.

[0014] The technical solution of the present invention is as follows:

[0015] A preparation method of 6β - N - methyl - naltrexamine specifically includes the following steps:

[0016] At room temperature, SM - 1 and methylamine reagent are added to the reaction solvent, and the temperature is controlled for reaction; then SM - 2 and hydrogen donor are added to the reaction solution, and after controlling the temperature until the reaction ends, through post - treatment, it is I.

[0017] The synthesis route is as follows:

[0018]

[0019] Preferred scheme: The methylamine reagent is one or more of methylamine gas, methylamine methanol solution, methylamine ethanol solution, methylamine tetrahydrofuran solution and methylamine hydrochloride.

[0020] Preferred scheme: According to the properties of the reaction substrate, a suitable solvent is selected. The reaction solvent is one of acetonitrile, chloroform, dichloromethane, N, N - dimethylacetamide, N, N - dimethylformamide, N - methyl - 2 - pyrrolidone, ethyl acetate, ethanol, methanol.

[0021] Preferred scheme: The hydrogen donor SM - 3 is specifically one or a combination of SM - 3 - 1, SM - 3 - 2, SM - 3 - 3, SM - 3 - 4, SM - 3 - 5, and SM - 3 - 5 is particularly preferred. The structural formulas of the related compounds are shown as follows:

[0022]

[0023] In a preferred embodiment, the molar ratio of SM-1 to methylamine, SM-2, and SM-3 in the feeding is 1: 2.5-6.0: 0.05-0.2: 1.05-1.4, and particularly preferably 1: 3.5: 0.1: 1.25.

[0024] In a preferred embodiment, the reaction temperature after adding methylamine is 15-40 °C, and particularly preferably 20-25 °C; the reaction temperature after adding SM-2 and the hydrogen donor is 30-60 °C, and particularly preferably 40-45 °C.

[0025] In a preferred embodiment, the post-treatment is as follows: after the reaction is completed, the reaction solution is concentrated under reduced pressure to dryness, added to purified water, and the pH is adjusted to 9-10 with concentrated ammonia water to form a precipitate. The obtained precipitate is filtered and then dried in vacuo to obtain the target product I.

[0026] Technical effects of the present invention:

[0027] The present invention provides a new method for preparing 6β-N-methyl-naltrexamine. This method is simple and easy to implement, and the yield and purity of the obtained product are relatively high, which is suitable for industrial production. Description of the drawings

[0028] Figure 1 is the 1H NMR spectrum of 6β-N-methyl-naltrexamine;

[0029] Figure 2 is the enlarged partial 1H NMR spectrum of 6β-N-methyl-naltrexamine;

[0030] Figure 3 is the enlarged partial 1H NMR spectrum of 6β-N-methyl-naltrexamine;

[0031] Figure 4 is the enlarged partial 1H NMR spectrum of 6β-N-methyl-naltrexamine;

[0032] Figure 5 is the 13C NMR spectrum of 6β-N-methyl-naltrexamine;

[0033] Figure 6 is the enlarged partial 13C NMR spectrum of 6β-N-methyl-naltrexamine;

[0034] Figure 7 is the HPLC purity spectrum of 6β-N-methyl-naltrexamine obtained in Example 6;

[0035] Figure 8 is the HPLC purity spectrum of 6β-N-methyl-naltrexamine obtained in Example 7. Detailed implementation manners

[0036] The present invention will be further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope claimed by the present invention.

[0037] 6β-N-methyl-naltrexamine structure confirmation data: See Figures 1 to 6 .

[0038] Among them 1 1H NMR (600 MHz, CDCl3) δ ppm 6.64 (1H, d, J = 8.1 Hz), 6.54 (1H, d, J = 8.0 Hz), 4.56 (1H, d, J = 7.56 Hz) can confirm the β configuration; (See Figure 3 local enlarged 1H NMR spectrum).

[0039] 6β-N-methyl-naltrexamine HPLC purity analysis: The relative retention time of 6β-N-methyl-naltrexamine is about 19 min; the relative retention time of 6α-N-methyl-naltrexamine is about 26 min or 27 min. (See Figure 7 、 Figure 8 )

[0040] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0041] Example 1

[0042] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20-25 °C for reaction. After detection that the reaction was completed, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 12.27 g, 0.125 mol) were added to the reaction solution, and the temperature was controlled at 40-45 °C for reaction. After detection that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 93.5% and an HPLC purity of 98.248%, and the isomer 6α-N-methyl-naltrexamine was 1.104%.

[0043] Example 2

[0044] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (2 mol / L, 125 ml), and the reaction was carried out while controlling the temperature at 25 - 30°C. After detecting that the reaction was completed, SM-2 (7.72 g, 0.01 mol) and SM-3-1 (32.29 g, 0.125 mol) were added to the reaction solution, and the reaction was carried out while controlling the temperature at 40 - 45°C. After detecting that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 88.5%, an HPLC purity of 98.214%, and the isomer 6α-N-methyl-naltrexamine being 1.135%.

[0045] Example 3

[0046] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine tetrahydrofuran solution (2 mol / L, 120 ml), and the reaction was carried out while controlling the temperature at 35 - 40°C. After detecting that the reaction was completed, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 12.27 g, 0.125 mol) were added to the reaction solution, and the reaction was carried out while controlling the temperature at 40 - 45°C. After detecting that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 87.6%, an HPLC purity of 97.864%, and the isomer 6α-N-methyl-naltrexamine being 1.154%.

[0047] Example 4

[0048] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine methanol solution (4 mol / L, 150 ml), and the reaction was carried out while controlling the temperature at 15 - 20°C. After detecting that the reaction was completed, SM-2 (7.72 g, 0.01 mol) and SM-3-2 (31.66 g, 0.125 mol) were added to the reaction solution, and the reaction was carried out while controlling the temperature at 40 - 45°C. After detecting that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 92.6%, an HPLC purity of 98.046%, and the isomer 6α-N-methyl-naltrexamine being 1.115%.

[0049] Example 5

[0050] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 152.5 ml), and the reaction was carried out at a controlled temperature of 15 - 20 °C. After detecting that the reaction was completed, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 12.27 g, 0.125 mol) were added to the reaction solution, and the reaction was carried out at a controlled temperature of 40 - 45 °C. After detecting that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 10 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 92.8%, an HPLC purity of 98.041%, and the isomer 6α-N-methyl-naltrexamine being 1.108%.

[0051] Example 6

[0052] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the reaction was carried out at a controlled temperature of 20 - 25 °C. After detecting that the reaction was completed, SM-2 (3.86 g, 0.005 mol) and SM-3-3 (12.51 g, 0.125 mol) were added to the reaction solution, and the reaction was carried out at a controlled temperature of 45 - 50 °C. After detecting that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 89.3%, an HPLC purity of 97.049%, and the isomer 6α-N-methyl-naltrexamine being 1.859%.

[0053] Example 7

[0054] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the reaction was carried out at a controlled temperature of 20 - 25 °C. After detecting that the reaction was completed, SM-2 (3.09 g, 0.004 mol) and cyclohexanone (SM-3-5, 12.27 g, 0.125 mol) were added to the reaction solution, and the reaction was carried out at a controlled temperature of 50 - 55 °C. After detecting that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 87.5%, an HPLC purity of 96.347%, and the isomer 6α-N-methyl-naltrexamine being 1.994%.

[0055] Example 8

[0056] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20 - 25 °C for reaction. After detection that the reaction was completed, SM-2 (15.45 g, 0.02 mol) and SM-3-4 (10.26 g, 0.125 mol) were added to the reaction solution, and the temperature was controlled at 35 - 40 °C for reaction. After detection that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 90.3%, an HPLC purity of 98.105%, and the isomer 6α-N-methyl-naltrexamine being 1.106%.

[0057] Example 9

[0058] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20 - 25 °C for reaction. After detection that the reaction was completed, SM-2 (16.22 g, 0.021 mol) and cyclohexanone (SM-3-5, 12.27 g, 0.125 mol) were added to the reaction solution, and the temperature was controlled at 35 - 40 °C for reaction. After detection that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 92.8%, an HPLC purity of 98.110%, and the isomer 6α-N-methyl-naltrexamine being 1.126%.

[0059] Example 10

[0060] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20 - 25 °C for reaction. After detection that the reaction was completed, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 10.31 g, 0.105 mol) were added to the reaction solution, and the temperature was controlled at 50 - 55 °C for reaction. After detection that the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 88.7%, an HPLC purity of 97.058%, and the isomer 6α-N-methyl-naltrexamine being 1.659%.

[0061] Example 11

[0062] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20-25 °C for reaction. After detection and completion of the reaction, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 9.81 g, 0.1 mol) were added to the reaction solution, and the temperature was controlled at 55-60 °C for reaction. After detection and completion of the reaction, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9.5 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 87.9%, an HPLC purity of 97.026%, and the isomer 6α-N-methyl-naltrexamine being 1.698%.

[0063] Example 12

[0064] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20-25 °C for reaction. After detection and completion of the reaction, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 13.74 g, 0.14 mol) were added to the reaction solution, and the temperature was controlled at 40-45 °C for reaction. After detection and completion of the reaction, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 10 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 92.6%, an HPLC purity of 97.846%, and the isomer 6α-N-methyl-naltrexamine being 1.241%.

[0065] Example 13

[0066] At room temperature, naltrexone (SM-1, 34.14 g, 0.1 mol) was added to a methylamine ethanol solution (4 mol / L, 87.5 ml), and the temperature was controlled at 20-25 °C for reaction. After detection and completion of the reaction, SM-2 (7.72 g, 0.01 mol) and cyclohexanone (SM-3-5, 14.72 g, 0.15 mol) were added to the reaction solution, and the temperature was controlled at 40-45 °C for reaction. After detection and completion of the reaction, the reaction solution was concentrated under reduced pressure to dryness, added to purified water (150 ml), and the pH was adjusted to 9 with concentrated ammonia water to form a precipitate. The obtained precipitate was filtered and dried in vacuo to obtain the target product I, with a yield of 91.2%, an HPLC purity of 98.011%, and the isomer 6α-N-methyl-naltrexamine being 1.243%.

Claims

1. A method for preparing a nalfurafine intermediate, characterized in that, At room temperature, SM-1 and the methylamine reagent are added to the reaction solvent, and the temperature is controlled for the reaction; then SM-2 and the hydrogen donor are added to the reaction solution. After the temperature is controlled until the reaction ends, through post-treatment, it is I; the synthetic route is as follows: ； The hydrogen donor SM-3 is specifically one or a combination of SM-3-1, SM-3-2, SM-3-3, SM-3-4, and SM-3-5; the structural formulas of the related compounds are shown as follows: 。 2. The method according to claim 1, wherein The methylamine reagent is one or more of methylamine gas, methylamine methanol solution, methylamine ethanol solution, methylamine tetrahydrofuran solution, and methylamine hydrochloride.

3. The method according to claim 1, characterized in that, The reaction solvent described: acetonitrile, chloroform, dichloromethane, N , N N,N-dimethylacetamide, N , N N,N-dimethylformamide, N 1-methyl-2-pyrrolidone, ethyl acetate, ethanol, methanol, or one of them.

4. The method according to claim 1, wherein The hydrogen donor SM-3 is specifically SM-3-5.

5. The method according to claim 1, wherein The molar ratio of SM-1, the methylamine reagent, SM-2, and SM-3 in the feed is 1:2.5 - 6.0:0.05 - 0.2:1.05 - 1.

4.

6. The method according to claim 1, characterized in that The reaction temperature after adding the methylamine reagent is 15 - 40 °C.

7. The method according to claim 1, wherein The reaction temperature after adding SM-2 and the hydrogen donor is 30 - 60 °C.

8. The method according to claim 1, wherein The post-treatment: after the reaction ends, the reaction solution is concentrated under reduced pressure to dryness, added to purified water, and the pH is adjusted to 9 - 10 with concentrated ammonia water to form a precipitate. The obtained precipitate is filtered and then dried in vacuo to obtain the target product I.

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