A synthesis method of deuterium labeled levamisole hydrochloride

Abstract

This invention discloses a method for synthesizing deuterium-labeled levamisole hydrochloride, comprising the following steps: (1) dissolving compound I in a solvent and reacting it with deuterium-labeled 2-bromoethanol under alkaline conditions to obtain intermediate II; (2) dissolving intermediate II in a solvent and reacting the two amino groups on intermediate II with the C=S bond in phosgene, N,N'-thiocarbonyl diimidazole, or carbon disulfide under alkaline conditions to obtain intermediate III; (3) adding intermediate III to an acidic solvent, where the S group reacts with the terminal OH group to form a ring, and then reacting it with hydrogen chloride to obtain compound IV, i.e., deuterium-labeled levamisole hydrochloride. This invention designs a novel method to synthesize deuterium-labeled levamisole hydrochloride for the first time, with a purity of over 99% and an isotopic abundance of up to 98.9%, providing a reference standard for the research and promotion of levamisole hydrochloride, and has practical application value.

Description

Technical Field

[0001] This invention relates to a method for preparing a compound, and more particularly to a method for synthesizing deuterium-labeled levamisole hydrochloride. Background Technology

[0002] Levamisole hydrochloride is the active levorotatory isomer of thiamazole hydrochloride, with an activity approximately 1-2 times that of the racemic thiamazole, and lower toxicity. It is used as an antiparasitic drug, a biological response modifier, and as an adjuvant in malignant diseases. Levamisole is effective against intestinal nematodes, especially in treating ascariasis, and is also used to treat hookworm infections. Its activity against adult worms and microfilariae of *Filaria bancroftian*, *Filaria malaria*, and *Onchocerca foetida* is higher than that of diethylcarbazine. It can also be used as adjuvant therapy for pneumonia, post-operative care after breast cancer surgery, or chemotherapy for acute leukemia and malignant lymphoma. It holds a significant share of the human and livestock pharmaceutical market.

[0003] Deuterium, as a stable isotope of hydrogen, plays an important role in the pharmaceutical field. Therefore, the synthesis methods of high-purity, high-isotope-abundance deuterium-labeled compounds for such active pharmaceutical ingredients are of great value. Furthermore, the products are crucial for pharmacokinetic and pharmacodynamic studies, and can also be used to investigate the mechanisms of certain impurities generated during drug storage. Summary of the Invention

[0004] Purpose of the invention: The present invention aims to provide a method for synthesizing deuterium-labeled levamisole hydrochloride.

[0005] Technical solution: The method for synthesizing deuterium-labeled levamisole hydrochloride according to the present invention includes the following steps:

[0006] (1) Compound I was dissolved in a solvent and subjected to a substitution reaction with deuterated 2-bromoethanol under alkaline conditions to give intermediate II;

[0007] (2) Dissolve intermediate II in a solvent. Under alkaline conditions, the two amino groups on intermediate II undergo a cyclization reaction with the C=S bonds in phosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide to obtain intermediate III.

[0008] (3) Add intermediate III to an acidic solvent, where S reacts with the terminal OH to form a ring, and then reacts with hydrogen chloride to give compound IV, namely deuterated levamisole hydrochloride;

[0009] The synthesis route is as follows:

[0010]

[0011] Preferably, the reaction temperature in step (1) is 0℃~50℃, and the reaction time is 8~48 hours. More preferably, the reaction temperature is 30℃, and the reaction time is 16 hours.

[0012] Preferably, in step (1), the molar ratio of compound I to deuterium-labeled 2-bromoethanol is 0.5 to 2:1. More preferably, the molar ratio is 0.5 to 1.5:1. Particularly preferably, the molar ratio is 0.9:1.

[0013] Preferably, in step (1), the solvent is DMF, DMAc, or acetonitrile, and the volume ratio of compound I to the solvent is 1:10 to 50. More preferably, the solvent is DMF or DMAc, with a volume ratio of 1:15 to 30. Most preferably, the solvent is DMAc, with a volume ratio of 1:25.

[0014] Preferably, in step (1), the alkali used in the alkaline conditions is sodium carbonate, cesium carbonate, sodium hydroxide, cesium hydroxide, triethylamine, or tetrabutylammonium hydroxide, and the molar ratio of raw material I to the alkali is 1:0.8-6. More preferably, cesium carbonate, cesium hydroxide, and tetrabutylammonium hydroxide are selected, with a molar ratio of 1:0.8-3. Particularly preferably, cesium carbonate is selected, with a molar ratio of 1:1.5.

[0015] In step (2), intermediate II undergoes two substitution reactions with phosgene or N,N'-thiocarbonyl diimidazole to form a cyclization ring; intermediate II undergoes two addition reactions with carbon disulfide to form a cyclization ring.

[0016] Preferably, in step (2), when phosgene or N,N'-thiocarbonyldiimidazole is used in the reaction, the reaction temperature is -20℃ to 20℃ and the reaction time is 1 to 4 hours. More preferably, the reaction temperature is -10℃ and the reaction time is 2 hours. When carbon disulfide is used, the reaction temperature is 60℃ to 100℃ and the reaction time is 18 to 48 hours.

[0017] Preferably, the molar ratio of intermediate II to phosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide is 1:0.8 to 7.

[0018] Preferably, in step (2), the solvent is dichloromethane, dichloroethane, tetrahydrofuran, a 50% aqueous methanol solution, a 50% aqueous ethanol solution, or isopropanol, and the volume ratio of intermediate II to the solvent is 1:5 to 60. More preferably, the solvent is dichloroethane, a 50% aqueous ethanol solution, or isopropanol, with a volume ratio of 1:10 to 30. Particularly preferably, the solvent is dichloroethane, with a volume ratio of 1:15.

[0019] Preferably, in step (2), the base used in the alkaline conditions is triethylamine, DIPEA, DBU, sodium carbonate, potassium carbonate, or cesium carbonate, and the molar ratio of intermediate II to the base is 1:1 to 6. Preferably, the base is triethylamine, DIPEA, or potassium carbonate, with a molar ratio of 1:1 to 3. Particularly preferably, the base is triethylamine, with a molar ratio of 1:3. The corresponding reagent is phosgene, N,N'-thiocarbonyldiimidazole, or carbon disulfide, and the molar ratio of intermediate II to the reagent is 1:0.8 to 7. Preferably, the corresponding reagent is phosgene or carbon disulfide, with a molar ratio of 1:0.8 to 4. Particularly preferably, the corresponding reagent is phosgene, with a molar ratio of 1:0.9.

[0020] Preferably, in step (3), the reaction time is 0.1 to 18 hours; when the acidic solvent is thionyl chloride or trifluoromethanesulfonic acid, the reaction temperature is 0°C to 80°C; when polyphosphoric acid is used, the reaction temperature is 80°C to 145°C; more preferably, the reaction temperature is 80°C and the reaction time is 3 hours.

[0021] Preferably, in step (3), the acidic solvent is thionyl chloride, trifluoromethanesulfonic acid, or polyphosphoric acid, with a volume ratio of 1:10 to 40. Particularly preferably, the acidic reagent is trifluoromethanesulfonic acid, and the volume ratio of intermediate III to the acidic solvent is 1:18.

[0022] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) It is the first to realize the synthesis of deuterium-labeled levamisole hydrochloride. Using deuterium-labeled 2-bromoethanol as raw material, a novel method for synthesizing deuterium-labeled levamisole hydrochloride was designed and implemented; (2) Through a large number of experiments, the optimal synthesis route and reaction conditions were screened out. The purity of the target product obtained can reach more than 99%, the isotope abundance can reach up to 98.9%, the total yield is 49%, and the deuterium atom utilization rate is close to 50%. It provides a reference standard for the research and promotion of levamisole hydrochloride and has practical application value. Attached Figure Description

[0023] Figure 1 A schematic diagram of the synthesis reaction process for deuterium-labeled levamisole hydrochloride;

[0024] Figure 2 The IR spectrum of the deuterated levamisole hydrochloride prepared in this invention;

[0025] Figure 3 The NMR spectrum of deuterium-labeled levamisole hydrochloride prepared in this invention;

[0026] Figure 4 The HPLC chromatogram of the deuterated labeled levamisole hydrochloride prepared in this invention;

[0027] Figure 5Mass spectrometry abundance of deuterium-labeled levamisole hydrochloride (IV). Detailed Implementation

[0028] The technical solution of the present invention will be further described below with reference to the embodiments.

[0029] Example 1

[0030] The synthesis route for intermediate II is as follows:

[0031]

[0032] Compound I was dissolved in a solvent, and after adding alkali, the mixture was stirred for 1 hour. Then, deuterium-labeled 2-bromoethanol was added, and the reaction continued. The reaction solution was filtered and concentrated to a crude product, which was then purified by column chromatography (stationary phase: silica gel; mobile phase: dichloromethane and ammonia-methanol gradient concentrations) to obtain intermediate II, [M+H]. + =185.2, yield and deuterium abundance are shown in Table 1 below.

[0033] Table 1

[0034]

[0035]

[0036] As shown in Table 1, the yields of the control group under conditions 1–4 were significantly lower than those under conditions 1–6. In comparison, condition 4 showed the highest reaction yield and the deuterium abundance was within the normal range.

[0037] Example 2

[0038] The synthesis route for intermediate III is as follows:

[0039]

[0040] Intermediate II, with a deuterium abundance of 99.1%, was dissolved in a solvent. A base and corresponding reagent were added, and the mixture was reacted and filtered (if solids were present). The filtrate was concentrated and then extracted again with an ethyl acetate-sodium bicarbonate aqueous solution. The extract was dried and concentrated to obtain the crude product. The crude product was purified by column chromatography (stationary phase: silica gel; mobile phase: dichloromethane and methanol gradient concentrations) to obtain intermediate III, [M+H]. + =227.1, the deuterium abundance and yield are shown in Table 2 below, where A represents phosgene, B represents N,N'-thiocarbonyldiimidazole, and C represents carbon disulfide.

[0041] Table 2

[0042]

[0043] As shown in Table 2, the yield of the control group under conditions 1-5 was significantly lower than that under conditions 1-5. In comparison, the reaction yield was the highest under condition 5, and the deuterium abundance was also within the normal range.

[0044] Example 3

[0045] The synthetic route for the synthesis of deuterium-labeled levamisole hydrochloride (IV) is as follows:

[0046]

[0047] Intermediate III, with a deuterium abundance of 99.0%, was dissolved in acid. The pH was adjusted to alkaline using hydrochloric acid and polyphosphoric acid under ice bath conditions. Then, it was extracted with ethyl acetate, dried, and concentrated to obtain the crude product to be purified. Under other conditions, the reaction solution was directly concentrated to obtain the crude product. The crude product was dissolved in ethyl acetate, washed with sodium bicarbonate aqueous solution, dried and concentrated in the organic phase to obtain the crude product to be purified. The crude product was purified by column chromatography (stationary phase: silica gel, mobile phase: dichloromethane and methanol gradient concentration), then dissolved in methanol, and the pH was adjusted to 1 by dissolving in methanol with hydrogen chloride. After concentration, deuterium-labeled levamisole hydrochloride (IV) was obtained. The deuterium abundance and yield are shown in Table 3 below.

[0048] Table 3

[0049]

[0050] As shown in Table 3, the yield under conditions 1-3 was significantly lower than that under conditions 1-7. Overall, condition 3 showed the highest reaction yield and the deuterium abundance was within the normal range.

[0051] Deuterium-labeled levamisole hydrochloride (IV) [M+H] + =209.1.

[0052] Figure 2 IR spectrum of deuterium-labeled levamisole hydrochloride (IV), infrared absorption (cm²) -1 ): 2862.08, 2753.03, 1569.05, 1523.83, 1305.54.

[0053] Figure 3 Deuterated levamisole hydrochloride (IV) 1 1H-NMR spectrum, 1H NMR spectrum (deuterium water, 400MHz): 7.49 (m, 5H), 5.76 (t, 1H), 4.28 (t, 1H), 3.72 (t, 1H).

[0054] Figure 4 The HPLC of deuterium-labeled levamisole hydrochloride (IV) is shown in the figure.

[0055] Figure 5Mass spectrometry abundance of deuterium-labeled levamisole hydrochloride (IV).

Claims

1. A method for synthesizing deuterium-labeled levamisole hydrochloride, characterized in that, Includes the following steps: (1) Compound I was dissolved in a solvent and subjected to a substitution reaction with deuterated 2-bromoethanol under alkaline conditions to give intermediate II; (2) Dissolve intermediate II in a solvent. Under alkaline conditions, the two amino groups on intermediate II undergo a cyclization reaction with the C=S bonds in phosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide to obtain intermediate III. (3) Add intermediate III to an acidic solvent, where S reacts with the terminal OH to form a ring, and then reacts with hydrogen chloride to give compound IV, namely deuterated levamisole hydrochloride; The synthesis route is as follows:

2. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, When phosgene or N,N'-thiocarbonyldiimidazole is used in the reaction described in step (2), the reaction temperature is -20℃ to 20℃; when carbon disulfide is used, the reaction temperature is 60℃ to 100℃.

3. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (2), the molar ratio of intermediate II to phosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide is 1:0.8-7.

4. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, The reaction temperature in step (1) is 0℃~80℃.

5. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (3), the acidic solvent should be thionyl chloride or trifluoromethanesulfonic acid, and the reaction temperature should be 0℃~80℃. When polyphosphoric acid is used, the reaction temperature should be 80℃~145℃.

6. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (1), the molar ratio of compound I to deuterated 2-bromoethanol is 0.5 to 2:

1.

7. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (1), the solvent is DMF, DMAc or acetonitrile, and the volume ratio of compound I to solvent is 1:10 to 50; the base used in the alkaline conditions is sodium carbonate, cesium carbonate, sodium hydroxide, cesium hydroxide, triethylamine or tetrabutylammonium hydroxide, and the molar ratio of raw material I to base is 1:0.8 to 6.

8. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (2), the solvent is dichloromethane, dichloroethane, tetrahydrofuran, 50% methanol aqueous solution, 50% ethanol aqueous solution, or isopropanol, and the volume ratio of intermediate II to solvent is 1:5 to 60.

9. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (2), the base used in the alkaline conditions is triethylamine, DIPEA, DBU, sodium carbonate, potassium carbonate or cesium carbonate, and the molar ratio of intermediate II to the base is 1:1 to 6.

10. The method for synthesizing deuterated levamisole hydrochloride according to claim 1, characterized in that, In step (3), the acidic solvent is thionyl chloride, trifluoromethanesulfonic acid or polyphosphoric acid, and the ratio of intermediate III to the acidic solvent is 1:10 to 40.

Images