Synthesis method of deuterium-labeled levamisole hydrochloride

Abstract

The invention discloses a synthetic method of deuterium-labeled levamisole hydrochloride, which comprises the following steps: (1) dissolving a compound I in a solvent, and carrying out substitution reaction on the compound I and deuterium-labeled 2-bromoethanol under an alkaline condition to obtain an intermediate II; (2) dissolving the intermediate II in a solvent, and carrying out cyclization reaction on two amino groups on the intermediate II and C = S bonds in thiophosgene, N, N '-thiocarbonyldiimidazole or carbon disulfide under an alkaline condition to obtain an intermediate III; and (3) adding the intermediate III into an acidic solvent, carrying out substitution reaction on S and terminal OH to form a ring, and then reacting with hydrogen chloride to obtain a compound IV, namely deuterium-labeled levamisole hydrochloride. The deuterium-labeled levamisole hydrochloride is synthesized for the first time by designing a brand new method, the purity can reach 99% or above, the isotope abundance can reach 98.9% at most, a reference standard product is provided for research, popularization and the like of levamisole hydrochloride, and the deuterium-labeled levamisole hydrochloride has practical application value.

Description

Technical Field

[0001] The invention relates to a method for preparing a compound, in particular to a method for synthesizing deuterium-labeled levamisole hydrochloride. Background Art

[0002] Levamisole hydrochloride is the active L-isomer of thiamidine hydrochloride, which is about 1 to 2 times more active than thiamidine (racemate) and has lower toxic side effects. It is used as an anti-insect drug, biological response modifier, and as an adjuvant in malignant diseases. Levamisole is effective against intestinal nematodes, especially for the treatment of ascariasis, and is also used to treat hookworm infections. Its activity against adult worms and microfilariae of Bancroftian filariasis, Malayan Brugia and Onchocerca volvulus is higher than that of ethopropazine. It can also be used as an adjuvant treatment for lung plague, breast cancer surgery, or acute leukemia and malignant lymphoma after chemotherapy. It occupies an important market share in human and livestock and poultry breeding drugs.

[0003] Deuterium atoms, as a stable isotope of hydrogen, play an important role in the pharmaceutical field. Therefore, the synthesis method of high-purity, high-isotope-abundance deuterium-labeled compounds of such APIs is of great value, and its products play an important role in drug dynamics and pharmacokinetic research, and can also study the mechanism of the generation of certain impurities 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 of the present invention comprises the following steps:

[0006] (1) dissolving compound I in a solvent, and reacting with deuterium-labeled 2-bromoethanol under alkaline conditions to obtain intermediate II;

[0007] (2) dissolving intermediate II in a solvent, and reacting the two amine groups on intermediate II with the C=S bond in thiophosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide under alkaline conditions to obtain intermediate III;

[0008] (3) adding intermediate III to an acidic solvent, causing S to undergo a substitution reaction with the terminal OH to form a ring, and then reacting with hydrogen chloride to obtain compound IV, i.e., deuterium-labeled levamisole hydrochloride;

[0009] The synthetic route is as follows:

[0010]

[0011] Preferably, the reaction temperature of step (1) is 0°C to 50°C, and the reaction time is 8 to 48 hours. Preferably, the reaction temperature is 30°C, 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. 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. Further preferably, the solvent is DMF or DMAc, and the volume ratio is 1:15 to 30. Most preferably, the solvent is DMAc, and the volume ratio is 1:25.

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

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

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

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

[0018] Preferably, 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 the solvent is 1:5 to 60. Preferably, the solvent is dichloroethane, 50% ethanol aqueous solution, isopropanol, and the volume ratio is 1:10 to 30. Particularly preferably, the solvent is dichloroethane, and the volume ratio is 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 1:1-6. Preferably, the base is triethylamine, DIPEA, potassium carbonate, and the molar ratio is 1:1-3. Particularly preferably, the base is triethylamine, and the molar ratio is 1:3. The corresponding reagent is thiophosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide, and the molar ratio of intermediate II to the reagent is 1:0.8-7. Preferably, the corresponding reagent is thiophosgene and carbon disulfide, and the molar ratio is 1:0.8-4. Particularly preferably, the corresponding reagent is thiophosgene, and the molar ratio is 1:0.9.

[0020] Preferably, in step (3), the reaction time is 0.1 to 18 hours; when thionyl chloride or trifluoromethanesulfonic acid is used as the reaction acidic solvent, the reaction temperature is 0°C to 80°C; when polyphosphoric acid is used, the reaction temperature is 80°C to 145°C, and 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, and the volume ratio is 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) the synthesis of deuterium-labeled levamisole hydrochloride is realized for the first time, and a new method for synthesizing deuterium-labeled levamisole hydrochloride is designed and implemented using deuterium-labeled 2-bromoethanol as a raw material; (2) the optimal synthesis route and reaction conditions are screened out through a large number of experiments, and the purity of the prepared target product can reach more than 99%, the isotope abundance can reach up to 98.9%, the total yield is 49%, and the utilization rate of deuterium atoms is close to 50%, which provides a reference standard for the research and promotion of levamisole hydrochloride, etc., and has practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a diagram of the synthesis reaction process of deuterium-labeled levamisole hydrochloride;

[0024] Figure 2 The IR spectrum of deuterium-labeled levamisole hydrochloride prepared by the present invention;

[0025] Figure 3 The NMR spectrum of deuterium-labeled levamisole hydrochloride prepared by the present invention;

[0026] Figure 4 The HPLC spectrum of deuterium-labeled levamisole hydrochloride prepared by the present invention;

[0027] Figure 5This is the mass spectrum abundance diagram of deuterium-labeled levamisole (IV) hydrochloride. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described below in conjunction with embodiments.

[0029] Example 1

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

[0031]

[0032] Compound I was dissolved in a solvent, and a base was added and stirred for 1 hour. Deuterium-labeled 2-bromoethanol was then added and the reaction continued. The reaction solution was filtered and concentrated to a crude product, which was purified by column chromatography (the stationary phase was silica gel, and the mobile phase was a gradient concentration of dichloromethane and ammonia methanol) 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 under conditions 1 to 4 of the control group were significantly lower than those under conditions 1 to 6. The reaction yield under condition 4 was the highest and the deuterium abundance was also in the normal range.

[0037] Example 2

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

[0039]

[0040] Take the intermediate II with a deuterium abundance of 99.1% and dissolve it in a solvent, add a base and a corresponding reagent, filter after the reaction (if there is solid), concentrate the filtrate, extract it again with ethyl acetate-sodium bicarbonate aqueous solution, dry and concentrate it to obtain a crude product, and purify the crude product by column chromatography (the stationary phase is silica gel, and the mobile phase is dichloromethane and methanol gradient concentration) to obtain the intermediate III, [M+H] + =227.1, the deuterium abundance and yield are shown in Table 2 below, where A represents thiophosgene, B represents N,N'-thiocarbonyldiimidazole, and C represents carbon disulfide.

[0041] Table 2

[0042]

[0043] As shown in Table 2, the yields under conditions 1 to 5 of the control group were significantly lower than those under conditions 1 to 5. The comprehensive comparison showed that the reaction yield under condition 5 was the highest, and the deuterium abundance was also in the normal range.

[0044] Example 3

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

[0046]

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

[0048] Table 3

[0049]

[0050] It can be seen from Table 3 that the yields under conditions 1 to 3 are significantly lower than those under conditions 1 to 7. The comprehensive comparison shows that the reaction yield under condition 3 is the highest and the deuterium abundance is also in the normal range.

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

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

[0053] Figure 3 Deuterium-labeled levamisole (IV) hydrochloride 1 H-NMR spectrum, H-NMR (deuterated water, 400 MHz): 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 (IV) hydrochloride is shown in the figure.

[0055] Figure 5This is the mass spectrum abundance diagram of deuterium-labeled levamisole (IV) hydrochloride.

Claims

1. A method for synthesizing deuterium-labeled levamisole hydrochloride, characterized in that: The following steps are involved: (1) dissolving compound I in a solvent, and reacting with deuterium-labeled 2-bromoethanol under alkaline conditions to obtain intermediate II; (2) dissolving intermediate II in a solvent, and reacting the two amine groups on intermediate II with the C=S bond in thiophosgene, N,N'-thiocarbonyldiimidazole or carbon disulfide under alkaline conditions to obtain intermediate III; (3) adding intermediate III to an acidic solvent, causing S to undergo a substitution reaction with the terminal OH to form a ring, and then reacting with hydrogen chloride to obtain compound IV, i.e., deuterium-labeled levamisole hydrochloride; The synthetic route is as follows:

2. The method for synthesizing deuterium-labeled levamisole hydrochloride according to claim 1, characterized in that: When thiophosgene or N,N'-thiocarbonyldiimidazole is used in the reaction of step (2), the reaction temperature is -20°C to 20°C; when carbon disulfide is used, the reaction temperature is 60°C to 100°C.

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

4. The method for synthesizing deuterium-labeled levamisole hydrochloride according to claim 1, characterized in that: The reaction temperature in step (1) is 0°C to 80°C.

5. The method for synthesizing deuterium-labeled levamisole hydrochloride according to claim 1, characterized in that: In step (3), the reaction temperature is 0°C to 80°C when thionyl chloride or trifluoromethanesulfonic acid is selected as the acidic solvent, and the reaction temperature is 80°C to 145°C when polyphosphoric acid is selected.

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

1.

7. The method for synthesizing deuterium-labeled 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 the solvent is 1:10-50; 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 the base is 1:0.8-6.

8. The method for synthesizing deuterium-labeled 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 the solvent is 1:5-60.

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

10. The method for synthesizing deuterium-labeled 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 1:10-40.

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