Preparation method of isavuconazole side chain intermediate C1

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an isavuconazole side chain intermediate C1. Comprising the following steps: dissolving (2-(methylamino) pyridine-3-yl) methyl-2-((t-butyloxycarboryl) (methyl) amino) acetate in an organic solvent, transferring into a reaction container, and then adding inorganic alkali; and dissolving chloroformic acid-1-chloroethyl ester in an organic solvent, dropwise adding the obtained solution into the reaction container, carrying out a thermal insulation reaction after the dropwise addition is completed, and after the reaction is completed, washing, drying and concentrating to obtain the isavuconazole side chain intermediate C1. According to the method, side reactions are effectively avoided, the reaction conditions are mild, the used reagents are commercially available high-purity products which are easy to obtain, the operation control is convenient, the reaction path is short, and the method is very suitable for industrial production; in addition, the method is safe, pollution-free, low in production risk, low in cost and environment-friendly; meanwhile, the post-treatment process is simple, and high purity and high total yield of the obtained product can be ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing an isavuconazole side chain intermediate C1. Background Art

[0002] Isavuconazole is an antifungal drug jointly developed by Basilea Pharmaceuticals of Switzerland and Astellas of Japan. Its water-soluble prodrug is its onium sulfate salt. As a new broad-spectrum triazole drug, isavuconazole sulfate has the following characteristics compared with other similar drugs: (1) Diversity of administration forms: Its drug ingredient is a water-soluble prodrug, which enables isavuconazole to be flexibly developed into oral and intravenous administration forms to meet the needs of different treatment scenarios. (2) Excellent pharmacokinetic properties: Isavuconazole exhibits high bioavailability and can be easily converted between oral and intravenous administration. Its pharmacokinetic characteristics include low clearance, long half-life, and wide distribution volume, which together constitute ideal conditions for the treatment of systemic fungal diseases. In addition, compared with voriconazole, isavuconazole has fewer drug interactions. (3) Broad-spectrum and highly effective antibacterial activity: In vitro antibacterial test results show that isavuconazole has excellent activity against a variety of yeasts such as Candida, Aspergillus, Mucor, Cryptococcus, etc., which is at least not lower than most other antifungal drugs. However, the sensitivity to Fusarium and Phaeohyphomycetes is relatively low. In the 2017 ECIL-6 "Guidelines for Invasive Candidiasis, Aspergillosis and Mucormycosis in Leukemia and Hematopoietic Stem Cell Transplantation Patients", isavuconazole is recommended as the first-line treatment for invasive aspergillosis. In the 2017 ESCMID-ECMM-ERS "Guidelines for the Diagnosis and Management of Aspergillosis", isavuconazole is recommended as the first-line treatment for invasive pulmonary aspergillosis.

[0003] Chinese patent CN1387529A discloses a method for preparing isavuconazole side chain intermediate C1, and its synthesis route is shown in Formula 1): ; Formula 1); As shown in Formula 1), in the initial reaction stage, both N-acylation and O-acylation reactions in compound 1 can occur in view of the high acylation activity of 1-chloroethyl chloroformate, so the generation of byproduct 2' is inevitable. At the same time, in this preparation method, compound 2 is directly reacted with BOC-sarcosine to prepare side chain compound 3 without separation and purification, resulting in the byproduct 2' continuing to produce impurities in subsequent steps. At the same time, compound 3 is in an oily form, which is not conducive to the removal of byproduct 2' and its related impurities.

[0004] Chinese patent CN113861107A also discloses a method for preparing isavuconazole side chain intermediate C1, and its synthetic route is similar to formula 1), which uses 2-chloro-3-pyridinemethanol as the starting material, adds homemade (3-hydroxymethyl-pyridin-2-yl)-methyl-carbamic acid 1-chloro-ethyl ester to prepare compound 2, and then adds BOC-sarcosine to continue the reaction. The purity of the final product is about 95%, but due to the long synthetic route and the fact that compound 2 is an oily substance and has not been effectively purified, the final overall yield is only about 70%.

[0005] Chinese patent CN106032356A discloses another method for preparing isavuconazole side chain intermediate C1, and its synthesis route is shown in Formula 2): ; Formula 2); In the synthetic route shown in Formula 2), the reaction order of the groups is changed, that is, compound 1 first reacts with BOC-sarcosine, and the product is purified by crystallization and then reacts with 1-chloroethyl chloroformate to obtain compound 3. However, in the second step of the synthetic route, impurity 1 is still generated in the process of preparing compound 3. Therefore, how to effectively avoid the occurrence of side reactions and ensure the purity of the product during the preparation of isavuconazole side chain intermediate C1 is of great practical significance. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing an isavuconazole side chain intermediate C1, which not only effectively avoids the occurrence of side reactions, but also has mild reaction conditions, and the reagents used are all easily available commercially available high-purity products, which are easy to operate and control, and the reaction path is short, which is very suitable for industrial production; in addition, the method is safe and pollution-free, has low production risks, low costs, and is environmentally friendly; at the same time, its post-treatment process is simple, which can ensure that the obtained product has high purity and high total yield.

[0007] The preparation method of the isavuconazole side chain intermediate C1 of the present invention comprises the following steps: (1) dissolving (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate in an organic solvent, then transferring it to a reaction vessel, and then adding an inorganic base as a catalyst; (2) dissolving 1-chloroethyl chloroformate in an organic solvent to obtain a 1-chloroethyl chloroformate solution; (3) Add 1-chloroethyl chloroformate solution dropwise into the reaction container, keep warm for reaction, and after the reaction is complete, wash, dry and concentrate to obtain isavuconazole side chain intermediate C1 (N-methyl-N-(3-[((N-tert-butyloxycarbonyl-N-methylamino)acetoxy)methyl]pyridin-2-yl)carbamic acid (1-chloroethyl) ester). The synthesis route is as follows: ; The organic solvent is one of dichloromethane, tetrahydrofuran, ethyl acetate or ether, preferably dichloromethane.

[0008] The inorganic base is one of sodium carbonate, potassium carbonate or cesium carbonate, preferably sodium carbonate.

[0009] The dropping temperature is 0-10°C.

[0010] The temperature of the insulation reaction is 0-10°C.

[0011] The insulation reaction time is 3 to 4 hours.

[0012] In the step (1), the molar volume ratio of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate to the organic solvent is 1:(1.5-1.8) mol / L.

[0013] In the step (2), the molar volume ratio of 1-chloroethyl chloroformate to the organic solvent for dissolution is 1: (0.3-0.5) mol / L.

[0014] The molar ratio of the (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butyloxycarbonyl)(methyl)amino)acetate to the inorganic base is 1:(1.3-1.5).

[0015] The molar ratio of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate to 1-chloroethyl chloroformate is 1:(1.3-1.5).

[0016] Compared with the prior art, the present invention has the following beneficial effects: (1) The preparation method of the isavuconazole side chain intermediate C1 of the present invention effectively avoids the occurrence of side reactions, has mild reaction conditions, and the reagents used are all commercially available products that are easy to obtain and have high purity, and are easy to operate and control. At the same time, the reaction path is short, which is conducive to industrial production; (2) The preparation method of the isavuconazole side chain intermediate C1 of the present invention is safe and pollution-free, has low production risk, low production cost, and is environmentally friendly; (3) The method for preparing the isavuconazole side chain intermediate C1 of the present invention has simple post-treatment, high purity of the obtained product and high overall yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The liquid chromatogram of the isavuconazole side chain intermediate C1 prepared in Example 1; Figure 2 The NMR spectrum of the isavuconazole side chain intermediate C1 prepared in Example 1; Figure 3 is a liquid chromatogram of the isavuconazole intermediate prepared using the isavuconazole side chain intermediate C1 of Example 1; Figure 4 The liquid chromatogram of the isavuconazole intermediate prepared by using the isavuconazole side chain intermediate C1 of Comparative Example 2. DETAILED DESCRIPTION

[0018] The present invention will be further described below with reference to the embodiments.

[0019] The raw materials used in the examples and comparative examples are conventional commercially available raw materials unless otherwise specified, and the process methods used in the examples and comparative examples are conventional methods in the art unless otherwise specified.

[0020] Example 1 The preparation method of the isavuconazole side chain intermediate C1 comprises the following steps: (1) 30.9 g (0.1 mol) of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate was dissolved in 180 mL of dichloromethane and then transferred to a reaction bottle, followed by the addition of 13.80 g (0.13 mol) of sodium carbonate as a catalyst; (2) Dissolve 18.6 g (0.13 mol) of 1-chloroethyl chloroformate in 40 mL of dichloromethane; (3) At 5°C, 1-chloroethyl chloroformate solution was added dropwise to the reaction bottle. After the addition was completed, the reaction was carried out at 5±5°C for 4 hours. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, 200 mL of purified water was added, and the mixture was washed with water for 0.5 hours. After standing for stratification, the aqueous phase was separated, and 200 mL of saturated sodium chloride solution was added to wash the organic phase. After washing, the organic phase was allowed to stand for stratification, and the aqueous phase was separated. The organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure at 35°C to obtain 39.9 g of an oily substance, which was the isavuconazole side chain intermediate C1. The purity was 98.8% as determined by HPLC.

[0021] The prepared isavuconazole side chain intermediate C1 was characterized by liquid chromatography and nuclear magnetic resonance, respectively. Figure 1~2shown.

[0022] Figure 1 The liquid chromatogram of the isavuconazole side chain intermediate C1 prepared in Example 1 is shown in Table 1. Figure 1 The corresponding liquid chromatography data, combined with Figure 1 As can be seen from Table 1, the characteristic peaks presented in the liquid chromatogram are clear and consistent with the peak shape of the existing commercially available standard product (N-methyl-N-(3-[((N-tert-butyloxycarbonyl-N-methylamino)acetoxy)methyl]pyridin-2-yl)carbamic acid (1-chloroethyl) ester of Shandong Yilite Biopharmaceutical Technology Co., Ltd.), indicating that the preparation method of the present invention can effectively synthesize the isavuconazole side chain intermediate C1, and the obtained product has high purity and low impurity content.

[0023] Table 1 Figure 1 Liquid chromatography data

[0024] Figure 2 The NMR spectrum of the isavuconazole side chain intermediate C1 prepared in Example 1 is Figure 2 It can be seen that the number and chemical shift of hydrogen atoms in the obtained NMR spectrum are consistent with the structural formula.

[0025] Example 2 The preparation method of the isavuconazole side chain intermediate C1 comprises the following steps: (1) 61.8 g (0.2 mol) of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate was dissolved in 300 mL of tetrahydrofuran, and then transferred to a reaction bottle, followed by the addition of 38.7 g (0.28 mol) of potassium carbonate as a catalyst; (2) Dissolve 37.2 g (0.26 mol) of 1-chloroethyl chloroformate in 130 mL of tetrahydrofuran; (3) At 2°C, 1-chloroethyl chloroformate solution was added dropwise to the reaction bottle. After the addition was completed, the reaction was carried out at 5±5°C for 3 hours. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, 300 mL of purified water was added, and the mixture was washed with water for 0.5 hours. After standing for stratification, the aqueous phase was separated, and 300 mL of saturated sodium chloride solution was added to wash the organic phase. After washing, the organic phase was allowed to stand for stratification, and the aqueous phase was separated. The organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure at 35°C to obtain 76.3 g of an oily substance, which was the isavuconazole side chain intermediate C1. The purity was 98.1% as determined by HPLC.

[0026] Example 3 The preparation method of the isavuconazole side chain intermediate C1 comprises the following steps: (1) 30.9 g (0.1 mol) of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate was dissolved in 180 mL of ethyl acetate and then transferred to a reaction bottle, followed by the addition of 15.90 g (0.15 mol) of sodium carbonate as a catalyst; (2) Dissolve 20.0 g (0.14 mol) of 1-chloroethyl chloroformate in 56 mL of ethyl acetate; (3) At 10°C, 1-chloroethyl chloroformate solution was added dropwise to the reaction bottle. After the addition was completed, the reaction was carried out at 5±5°C for 4 hours. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, 200 mL of purified water was added, and the mixture was washed with water for 0.5 hours. After standing for stratification, the aqueous phase was separated, and 200 mL of saturated sodium chloride solution was added to wash the organic phase. After washing, the organic phase was allowed to stand for stratification, the aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure at 35°C to obtain 36.0 g of an oily substance, which was the isavuconazole side chain intermediate C1. The purity was 98.5% as determined by HPLC.

[0027] Comparative Example 1 The preparation method of the isavuconazole side chain intermediate C1 comprises the following steps: (1) 30.9 g (0.1 mol) of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate was dissolved in 180 mL of dichloromethane and then transferred to a reaction bottle, followed by the addition of 12.60 g (0.15 mol) of sodium bicarbonate as a catalyst; (2) Dissolve 18.6 g (0.13 mol) of 1-chloroethyl chloroformate in 40 mL of dichloromethane; (3) At 5°C, 1-chloroethyl chloroformate solution was added dropwise to the reaction bottle. After the addition was completed, the reaction was carried out at 5±5°C for 6 hours. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, 200 mL of purified water was added, and the mixture was washed with water for 0.5 hours. After standing for stratification, the aqueous phase was separated, and 200 mL of saturated sodium chloride solution was added to wash the organic phase. After washing, the organic phase was allowed to stand for stratification, and the aqueous phase was separated. The organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure at 35°C to obtain 29.9 g of an oily substance, which was the isavuconazole side chain intermediate C1. The purity was 96.8% as determined by HPLC.

[0028] In this comparative example, sodium bicarbonate is used as an inorganic base. Since it has a weak alkalinity and is a monobasic base, the catalytic reaction speed is slow. During the reaction, more water will be generated, which will cause the degradation of the raw materials. Therefore, the entire reaction process is slow and the loss of raw materials is high.

[0029] Comparative Example 2 The preparation method of the isavuconazole side chain intermediate C1 comprises the following steps: (1) 30.9 g (0.1 mol) of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate was dissolved in 180 mL of ethyl acetate and then transferred to a reaction bottle, followed by the addition of 18.1 g (0.14 mol) of diisopropylethylamine as a catalyst; (2) Dissolve 20.0 g (0.14 mol) of 1-chloroethyl chloroformate in 56 mL of ethyl acetate; (3) At 5°C, 1-chloroethyl chloroformate solution was added dropwise to the reaction bottle. After the addition was completed, the reaction was carried out at 5±5°C for 4 hours. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, 200 mL of purified water was added, and the mixture was washed with water for 0.5 hours. After standing for stratification, the aqueous phase was separated, and 200 mL of saturated sodium chloride solution was added to wash the organic phase. After washing, the organic phase was allowed to stand for stratification, the aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure at 35°C to obtain 43.6 g of an oily substance, which was the isavuconazole side chain intermediate C1. The purity was 98.7% as determined by HPLC.

[0030] In this comparative example, diisopropylethylamine was used as a catalyst, and the reaction process was normal. However, the yield of the oil after concentration was higher than the theoretical yield. This was because the nitrogen atom contained in the molecular structure of diisopropylethylamine would also react with 1-chloroethyl chloroformate to generate impurities. The impurities overlapped with the peak position of the isavuconazole side chain intermediate C1 on the liquid chromatography (HPLC) graph, making it difficult to accurately distinguish the isavuconazole side chain intermediate C1 from the generated impurities in the product analysis, resulting in a higher apparent yield of the oil.

[0031] The isavuconazole side chain intermediate C1 prepared in Example 1 and Comparative Example 2 was used to prepare the isavuconazole intermediate. The preparation method was based on the "Study on the Synthesis of Isavuconazonium Sulfate" written by Song Haichao.

[0032] The obtained isavuconazole intermediate product was detected by liquid chromatography, and its spectrum was as follows: Figure 3~4 As shown in the figure, RT19.89±0.02min corresponds to the isavuconazole side chain intermediate C1, and RT21.63±0.04min corresponds to the isavuconazole intermediate product. Figure 3~4 By comparing and analyzing, it can be clearly seen that compared with Figure 3 The peak shape in Figure 4There is an obvious impurity peak (RT21.007min) on the spectrum shown, which corresponds to the accumulation of impurities generated by the reaction of diisopropylethylamine and 1-chloroethyl chloroformate in subsequent reactions. At the same time, due to the presence of impurities in the raw material isavuconazole side chain intermediate C1, the raw material consumption is reduced, so there is more raw material residue in the prepared isavuconazole intermediate. Therefore, the isavuconazole side chain intermediate C1 is Figure 4 The peak area in Figure 3 The peak area in .

[0033] This result further confirmed the previous speculation that although the introduction of diisopropylethylamine did not directly affect the reaction process, it led to an increase in the impurity content in the subsequent product, which not only affected the purity of the product and reduced the yield, but also increased the difficulty and cost of post-processing.

Claims

1. A method for preparing isavuconazole side chain intermediate C1, characterized in that: The following steps are involved: (1) dissolving (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate in an organic solvent, then transferring it to a reaction vessel, and then adding an inorganic base as a catalyst; (2) dissolving 1-chloroethyl chloroformate in an organic solvent to obtain a 1-chloroethyl chloroformate solution; (3) Add 1-chloroethyl chloroformate solution dropwise into the reaction container, keep warm for reaction, and after the reaction is completed, wash, dry and concentrate to obtain isavuconazole side chain intermediate C1.

2. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The organic solvent is one of dichloromethane, tetrahydrofuran, ethyl acetate or ether.

3. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The inorganic base is one of sodium carbonate, potassium carbonate or cesium carbonate.

4. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The dropping temperature is 0-10°C.

5. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The temperature of the insulation reaction is 0-10°C.

6. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The insulation reaction time is 3 to 4 hours.

7. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: In the step (1), the molar volume ratio of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate to the organic solvent is 1:(1.5-1.8) mol / L.

8. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: In the step (2), the molar volume ratio of 1-chloroethyl chloroformate to the organic solvent is 1: (0.3-0.5) mol / L.

9. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The molar ratio of the (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butyloxycarbonyl)(methyl)amino)acetate to the inorganic base is 1:(1.3-1.5).

10. The method for preparing the isavuconazole side chain intermediate C1 according to claim 1, characterized in that: The molar ratio of (2-(methylamino)pyridin-3-yl)methyl-2-((tert-butoxycarbonyl)(methyl)amino)acetate to 1-chloroethyl chloroformate is 1:(1.3-1.5).

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