Synthesis method of dalbavancin demethylated B2 nitrosamine

Abstract

The invention relates to the technical field of medicine preparation, in particular to a synthesis method of dalbavancin demethylated B2 nitrosamine. The synthesis method comprises the following steps: S1, taking a dalbavancin precursor A-40926-B0 as a raw material, and carrying out methylation reaction to obtain an intermediate I; s2, performing esterification protection on the intermediate I to obtain an intermediate II; s3, carrying out condensation reaction on the intermediate II and 3-methylaminopropylamine to obtain an intermediate III, and carrying out alkaline hydrolysis to obtain an intermediate IV; s4, carrying out nitrosation on the intermediate IV through a nitrosation reagent to obtain dalbavancin demethylated B2 nitrosamine; the synthesis method is high in reaction yield, the purity of the demethylated B2 nitrosamine compound of the dalbavancin can be as high as that of the dalbavancin, and a reference substance is provided for quality control of the dalbavancin.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a method for synthesizing dapavancin demethyl B2 nitrosamine. Background Technology

[0002] Dapavancin, also known as dauguin, is a long-acting semi-synthetic lipopeptide glycopeptide antibiotic with a half-life of 149-250 hours in vivo. Due to its unique long-acting properties and strong activity against drug-resistant Gram-positive bacteria, it plays an important role in the treatment of acute bacterial skin and skin structure infections. Several patents exist for the preparation of dauvancin: WO2022148868A1 and CN109467592B both involve the protective esterification of the dauvancin precursor A-40926, the amidation condensation of 3-dimethylaminopropylamine with the parent nucleus, and deprotection hydrolysis to obtain dauvancin.

[0003] Genotoxic impurities refer to compounds that can directly or indirectly damage DNA, cause gene mutations, or cause cancer, and imine impurities are typical genotoxic impurities. Nitrosamine impurities, which are highly carcinogenic, have attracted the common attention of regulatory agencies worldwide. Nitrosamine impurities are listed as "cohorts of concern" in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7(R1) (Assessing and controlling DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risks) [1]. These substances can significantly increase the risk of cancer even at extremely low doses (usually in the nanogram range), and are therefore classified as the highest risk level. The Center for Drug Evaluation of the National Medical Products Administration of China issued the "Technical Guidelines for Research on Nitrosamine Impurities in Chemical Drugs (Trial Implementation)," which proposed that the control of nitrosamine impurities in drugs should be based on compliance with the requirements of ICH M7(R1) to ensure that the levels of such impurities in active pharmaceutical ingredients and formulations are below acceptable limits. Meanwhile, the FDA released "Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)," strengthening the regulation of nitrosamine impurities in all approved and under-review drugs. The guidance identifies nine nitrosamine impurities in dapavancin derivatives, and dapavancin demethyl B2 nitrosamine is one of these nine impurities. The document explicitly states that the acceptable intake limit for dapavancin demethyl B2 nitrosamine is 1500 ng / day, as shown in the table below:

[0004]

[0005] Therefore, accurate detection of dapavancin demethyl β2 nitrosamine in dapavancin is of great practical significance for the quality detection and quality control of dapavancin.

[0006] Dabavancin demethyl B2-nitrosamine is one of the nitrosamine impurities in the dabavancin class. Currently, no synthetic method for dabavancin demethyl B2-nitrosamine has been reported. The precursor compounds for the synthesis of dabavancin demethyl B2-nitrosamine have complex structures, contain sensitive groups, and the reaction process is prone to producing many impurities, making purification difficult and presenting technical challenges. Therefore, it is currently impossible to provide a compliant reference standard for the quality control of this impurity. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for synthesizing dapavancin demethyl B2 nitrosamine, which is used to provide an impurity reference standard for quality control.

[0008] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for synthesizing dapavancin demethyl B2 nitrosamine, comprising the following steps: S1: Using dapavancin precursor A-40926-B0 as a raw material, a methylation reaction was carried out to obtain intermediate I; S2: The intermediate I is protected by esterification to obtain intermediate II; S3: The intermediate II is condensed with 3-methylaminopropylamine to obtain intermediate III, and then intermediate IV is obtained by alkaline hydrolysis; S4: Nitrosify the intermediate IV with a nitrosating agent to obtain dabavancin demethyl B2 nitrosamine; The structural formula of A-40926-B0 is shown in Formula (1), the structural formula of intermediate I is shown in Formula (2), the structural formula of intermediate II is shown in Formula (3), the structural formula of intermediate III is shown in Formula (4), the structural formula of intermediate IV is shown in Formula (5), and the structural formula of Bavancin demethyl B2 nitrosamine is shown in Formula (6). Equation (1); Equation (2); Equation (3); Equation (4); Equation (5); Equation (6).

[0009] The beneficial effects of this invention are as follows: the synthesis method of this invention has a high reaction yield and can obtain a compound with a purity as high as that of dapavancin demethyl B2 nitrosamine, providing a reference standard for the quality control of dapavancin. Attached Figure Description

[0010] Figure 1 This is the hydrogen spectrum of demethylated B2-nitrosamine from the embodiments of the present invention; Figure 2 This is the carbon spectrum of bavancin demethyl B2 nitrosamine in an embodiment of the present invention; Figure 3 This is the mass spectrum of bavancin demethyl B2 nitrosamine in an embodiment of the present invention; Figure 4 The infrared spectrum of demethylated B2 nitrosamine from the embodiments of the present invention is shown. Detailed Implementation

[0011] To explain in detail the technical content, objectives, and effects of the present invention, the following description is provided in conjunction with the embodiments and accompanying drawings.

[0012] A method for synthesizing dapavancin demethyl B2 nitrosamine includes the following steps: S1: Using dapavancin precursor A-40926-B0 as a raw material, a methylation reaction was carried out to obtain intermediate I; S2: Esterification protection of intermediate I yields intermediate II; S3: Intermediate II is condensed with 3-methylaminopropylamine to obtain intermediate III, and then intermediate IV is obtained by alkaline hydrolysis; S4: Nitrosamine intermediate IV by passing it through a nitrosating agent to obtain dabavancin demethyl B2 nitrosamine; The structural formula of A-40926-B0 is shown in Formula (1), the structural formula of intermediate I is shown in Formula (2), the structural formula of intermediate II is shown in Formula (3), the structural formula of intermediate III is shown in Formula (4), the structural formula of intermediate IV is shown in Formula (5), and the structural formula of Bavancin demethyl B2 nitrosamine is shown in Formula (6). Equation (1); Equation (2); Equation (3); Equation (4); Equation (5); Equation (6).

[0013] As can be seen from the above description, the beneficial effects of the present invention are as follows: Under normal conditions, the formation pathway of dapavancin demethylated B2 nitrosamine involves the removal of a methyl group from the side chain of dapavancin B2 to generate dedapavancin demethylated B2, which is then nitrosated to produce dapavancin demethylated B2 nitrosamine. However, the inventors' research has shown that the demethylation reaction is difficult to control, making it hard to accurately remove the target methyl group, resulting in numerous reaction impurities. Furthermore, the extremely low proportion of the dapavancin B2 component in dapavancin further complicates the preparation of this compound.

[0014] The synthetic method of this invention uses readily available dapavancin precursor A-40926-B0 as a raw material. A-40926-B2 is synthesized via methylation, followed by the directed synthesis of dapavancin demethylated B2. The carboxyl group is protected by esterification, and then it undergoes a condensation reaction with 3-methylaminopropylamine. After hydrolysis, dapavancin demethylated B2 is obtained. Dapavancin demethylated B2 is then nitrosated to obtain dapavancin demethylated B2 nitrosamine. The synthetic route is as follows: .

[0015] This synthetic method has high yield and high purity, and can provide a reference standard for the quality control of dapavancin, providing important guidance for safe drug use.

[0016] Further, the specific steps of S1 are as follows: A-40926-B0 is dissolved in a solvent and then a methylating agent is added to react. After the reaction is complete, intermediate I is obtained.

[0017] As can be seen from the above description, S1 achieves methylation.

[0018] Further, after the S1 reaction is complete, water is added and the pH is adjusted to 2-3. After crystallization, filtration, and drying, intermediate I is obtained.

[0019] As can be seen from the above description, purification is carried out after the reaction is completed in order to improve the purity of the final product.

[0020] Furthermore, the methylating agent in S1 is selected from one or more of iodomethane, bromomethane, dimethyl sulfate, formaldehyde, and paraformaldehyde. Formaldehyde is preferred.

[0021] Furthermore, when the methylating agent of S1 is one or more of iodomethane, bromomethane and dimethyl sulfate, an alkali is added during the reaction of S1; Furthermore, when the methylating agent of S1 is formaldehyde and / or paraformaldehyde, a reducing agent, or a reducing agent and an acid, are added during the reaction of S1.

[0022] Furthermore, the reducing agent in S1 is selected from one or more of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. Sodium cyanoborohydride is preferred.

[0023] Furthermore, the solvent in S1 is selected from one or more of methanol, ethanol, DMF (N,N-dimethylformamide), acetone, and dichloromethane.

[0024] Furthermore, the base in S1 is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, and triethylamine.

[0025] Furthermore, the acid in S1 is selected from acetic acid or formic acid.

[0026] Furthermore, the reaction temperature of S1 is 15~80°C. Preferably, it is 30~80°C, more preferably 50~70°C.

[0027] As can be seen from the above description, the reaction temperature of S1 is relatively low, which affects the reaction rate, while the reaction temperature is relatively high, which makes it easier for side reactions to occur.

[0028] Furthermore, in S1, the molar ratio of A-40926-B0 to the methylating agent is 1:(0.8~10).

[0029] Furthermore, in S1, the molar ratio of A-40926-B0 to the reducing agent is 1:(0.8~5).

[0030] Furthermore, in S1, the reaction time is 2~6 hours.

[0031] Furthermore, the formaldehyde is an aqueous solution of formaldehyde, with a concentration of 20-45%, preferably 30-45%.

[0032] Further, the specific steps of S1 are as follows: A-40926-B0 is dissolved in a solvent, and then formaldehyde and sodium cyanoborohydride are added. The reaction is carried out at 50~70℃. After the reaction is completed, intermediate I is obtained.

[0033] Further, the specific steps of S2 are as follows: intermediate I is added to isopropanol, sulfuric acid is added to react, and intermediate II is obtained.

[0034] As can be seen from the above description, S2 esterifies intermediate I to achieve carboxyl protection.

[0035] Furthermore, the sulfuric acid in S2 is concentrated sulfuric acid.

[0036] Further, after the S2 reaction is complete, water is added and the pH is adjusted to 7.0~8.0. After crystallization, filtration, and drying, intermediate II is obtained.

[0037] As can be seen from the above description, purification is carried out after the reaction is completed in order to improve the purity of the final product.

[0038] Furthermore, the reaction temperature of S2 is 8~12℃.

[0039] As can be seen from the above description, a lower reaction temperature affects the reaction rate, while a higher reaction temperature is more likely to cause side reactions.

[0040] Furthermore, the mass ratio of A-40926-B0 to isopropanol in S2 is 10:(50~100); the molar ratio of A-40926-B0 to sulfuric acid is 1:(5~20).

[0041] Further, the specific steps of S3 are as follows: after dissolving intermediate II in a solvent, TBTU (O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate), HOBT (1-hydroxyphenyltriazole) and 3-methylaminopropylamine are added to react and obtain intermediate III reaction solution; alkali is added to intermediate III reaction solution to perform hydrolysis and obtain intermediate IV.

[0042] As can be seen from the above description, the present invention selects 3-methylaminopropylamine for condensation reaction, and after condensation, a secondary aminomethyl group of the target side chain is obtained, which can be subjected to nitrosation reaction.

[0043] Furthermore, the solvent in S3 is DMF.

[0044] Furthermore, the molar ratio of A-40926-B0 to TBTU, HOBT and 3-methylaminopropylamine is 1:(0.8~2):(0.8~2):(0.8~2). Further, in S3, after dissolving intermediate II in a solvent, TBTU, HOBT and 3-methylaminopropylamine are added to carry out the reaction for 3-7 hours.

[0045] Furthermore, the base in S3 is selected from sodium hydroxide or potassium hydroxide.

[0046] Furthermore, the molar ratio of the base in A-40926-B0 to that in S3 is 1:(1-3).

[0047] Furthermore, the hydrolysis reaction temperature in S3 is 15~35℃, and the reaction time is 0.5~2h.

[0048] Further, after the hydrolysis of S3 is complete, water is added and the pH is adjusted to 7.0~8.0. After crystallization, filtration, and drying, intermediate IV is obtained.

[0049] As can be seen from the above description, purification is carried out after the reaction is completed in order to improve the purity of the final product.

[0050] Further, the specific steps of S4 are as follows: intermediate IV is dissolved in a solvent, a nitrosating agent is added, and then the pH of the solution is adjusted to 2-4 to carry out the reaction, so as to obtain dabavancin demethyl B2 nitrosamine.

[0051] Furthermore, the concentration of the nitrifying agent in S4 is 1~2 mol / L.

[0052] Furthermore, the solvent in S4 is preferably acetonitrile.

[0053] Furthermore, the nitrosating agent is sodium nitrite. Furthermore, the molar ratio of the nitrifying agent to intermediate I in S4 is (1:1) to (20:1). For example, it can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. Further, after the S4 reaction is complete, water is added and the pH is adjusted to 7.0~8.0. After crystallization, filtration, and drying, dabavancin demethyl B2 nitrosamine crystal powder is obtained.

[0054] As can be seen from the above description, purification is carried out after the reaction is completed in order to improve the purity of the final product.

[0055] The purity of dabavancin demethyl B2 nitrosamine obtained by the method of this invention is >97%, which is significantly higher than the impurity reference standard of impurity purity ≥95%.

[0056] All reagents involved in this invention are commercially available. A-40926-B0 can be obtained commercially or prepared by referring to the method in CN115160409B.

[0057] The A-40926-B0 in the following examples was prepared according to the method of CN115160409B.

[0058] Example 1 of the present invention is a method for synthesizing dapavancin demethyl β2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, purity ≥80%, 4.58mmol, 1eq) to the reaction flask and dissolve it in 500ml DMF. Add triethylamine (0.70g, 6.87mmol, 1.5eq) and iodomethane (0.98g, 6.87mmol, 1.5eq). React at 30℃ for 4h. Add 2500ml water and adjust the pH to 2.5 with hydrochloric acid. Crystallize and filter to obtain intermediate I crystal powder (single-step yield 55%).

[0059] S2: Add intermediate I and isopropanol (80 mL) to the reaction flask. The suspension of isopropanol and A-40926 complex in the reaction flask is pre-cooled to 5°C. Add concentrated sulfuric acid (4.52 g, 46 mmol, 10 eq) solution dropwise to carry out the reaction. After the reaction is completed at 10°C, add 400 mL of water, adjust the pH to 7, crystallize, filter, and dry to obtain intermediate II.

[0060] S3: Add DMF (80 mL) to the reaction flask, add intermediate II to dissolve, add TBTU (1.77 g, 5.52 mmol, 1.2 eq), HOBT (0.76 g, 5.52 mmol, 1.2 eq) and 98 mL (39.20 g, 5.52 mmol, 1 eq) of 3-methylaminopropylamine. After reacting for 5 h, intermediate III reaction solution is obtained. Add 9.2 mL of 1 mol / L NaOH (0.37 g, 9.20 mmol, 2 eq), control the temperature at 20 °C, react for 1 h, add 400 mL of water, adjust the pH to 7, crystallize, filter, and dry to obtain intermediate IV.

[0061] S4: Dissolve intermediate IV in 200 ml of acetonitrile, add 9.16 ml of 2M sodium nitrite (0.63 g, 9.16 mmol, 2 eq), adjust the pH to 3.0 with hydrochloric acid, react at room temperature for 3 h, add 1000 ml of water, adjust the pH to 7.0, crystallize and filter to obtain crude dabavancin demethyl B2 nitrosamine.

[0062] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl B2 nitrosamine (2.55 g, total molar yield 34%, purity 97.68%).

[0063] The structural formulas of A-40926-B0 are shown in Formula (1), intermediate I in Formula (2), intermediate II in Formula (3), intermediate III in Formula (4), intermediate IV in Formula (5), and Bavancin demethylated B2 nitrosamine in Formula (6). The 1H NMR spectrum of the synthesized Bavancin demethylated B2 nitrosamine in Example 1 is shown in [reference needed]. Figure 1 The carbon spectrum is shown below. Figure 2 Mass spectrum can be found Figure 3 Infrared spectrum (see) Figure 4 .

[0064] Example 2 of the present invention is a method for synthesizing dapavancin demethyl B2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, 80% purity, 4.58mmol, 1eq) to the reaction flask and dissolve it in 500ml of methanol. Add formaldehyde water (40% concentration, 1.52g, 22.9mmol, 5eq), acetic acid (0.027g, 0.46mmol, 0.1eq), and sodium cyanoborohydride (0.43g, 8.87mmol, 1.5eq). React at 30℃ for 4h. Add 2500ml of water and adjust the pH to 2.5 with hydrochloric acid. Crystallize and filter to obtain intermediate I crystal powder (single-step yield 62%).

[0065] S2: This step is the same as S2 in Example 2.

[0066] S3: This step is the same as S3 in Example 2.

[0067] S4: This step is the same as S4 in Example 2.

[0068] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl B2 nitrosamine (2.85 g, molar yield 38%, purity 97.22%).

[0069] Example 3 of the present invention is a method for synthesizing dapavancin demethyl B2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, 80% purity, 4.58mmol, 1eq) to the reaction flask and dissolve it in 500ml of methanol. Add 15.4ml of 5% sodium bicarbonate solution (0.77g, 9.16mmol, 2eq), and add dimethyl sulfate (0.69g, 5.50mmol, 1.2eq). React at 30℃ for 2h. Add 2500ml of water, adjust the pH to 2.5 with hydrochloric acid, crystallize and filter to obtain intermediate I crystal powder (single-step yield 52%).

[0070] S2: This step is the same as S2 in Example 2.

[0071] S3: This step is the same as S3 in Example 2.

[0072] S4: This step is the same as S4 in Example 2.

[0073] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl B2 nitrosamine (2.40 g, total molar yield 32%, 96.94%).

[0074] Example 4 of the present invention is a method for synthesizing dapavancin demethyl B2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, 80% purity, 4.58mmol, 1eq) to a reaction flask and dissolve it in 500ml of methanol. Add formaldehyde solution (40% concentration, 1.52g, 22.9mmol, 5eq), acetic acid (0.027g, 0.46mmol, 0.1eq), and sodium cyanoborohydride (0.43g, 8.87mmol, 1.5eq). React at 60℃ for 4h. Add 2500ml of water and adjust the pH to 2.5 with hydrochloric acid. Crystallize and filter to obtain intermediate I crystal powder (single-step yield 72%).

[0075] S2: This step is the same as S2 in Example 2.

[0076] S3: This step is the same as S3 in Example 2.

[0077] S4: This step is the same as S4 in Example 2.

[0078] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl B2 nitrosamine (3.22 g, total molar yield 44%, 97.49%).

[0079] Example 5 of the present invention is a method for synthesizing dapavancin demethyl B2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, 80% purity, 4.58mmol, 1eq) to the reaction flask and dissolve it in 500ml of methanol. Add formaldehyde water (40% concentration, 1.52g, 22.9mmol, 5eq), acetic acid (0.027g, 0.46mmol, 0.1eq), and sodium cyanoborohydride (0.43g, 8.87mmol, 1.5eq). After the reaction is complete at 15℃, add 2500ml of water and adjust the pH to 2.5 with hydrochloric acid. Crystallize and filter to obtain intermediate I crystal powder (single-step yield 26%).

[0080] S2: This step is the same as S2 in Example 2.

[0081] S3: This step is the same as S3 in Example 2.

[0082] S4: This step is the same as S4 in Example 2.

[0083] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl β2 nitrosamine (1.2 g, total molar yield 16%, 98.02%).

[0084] Example 6 of the present invention is a method for synthesizing dapavancin demethyl B2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, 80% purity, 4.58mmol, 1eq) to the reaction flask and dissolve it in 500ml of methanol. Add formaldehyde water (30% concentration, 1.52g, 22.9mmol, 5eq) and sodium triacetoxyborohydride (2.91g, 13.74mmol, 3eq). React at 60℃ for 8h. Add 2500ml of water and adjust the pH to 2.5 with hydrochloric acid. Crystallize and filter to obtain intermediate I crystal powder (single-step yield 46%).

[0085] S2: This step is the same as S2 in Example 2.

[0086] S3: This step is the same as S3 in Example 2.

[0087] S4: This step is the same as S4 in Example 2.

[0088] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl B2 nitrosamine (2.10 g, total molar yield 28%, 97.14%).

[0089] Example 7 of the present invention is a method for synthesizing dapavancin demethyl B2 nitrosamine, the specific steps of which are as follows: S1: Add A-40926-B0 (10g, 80% purity, 4.58mmol, 1eq) to the reaction flask and dissolve it in 500ml of methanol. Add formaldehyde water (30% concentration, 1.52g, 22.9mmol, 5eq) and sodium borohydride (0.346g, 9.16mmol, 2eq). React at 60℃ for 8h. Add 2500ml of water and adjust the pH to 2.5 with hydrochloric acid. Crystallize and filter to obtain intermediate I crystal powder (single-step yield 36%).

[0090] S2: This step is the same as S2 in Example 2.

[0091] S3: This step is the same as S3 in Example 2.

[0092] S4: This step is the same as S4 in Example 2.

[0093] S5: The crude product was purified by reversed-phase silica gel chromatography, crystallized, and lyophilized to obtain dabavancin demethyl B2 nitrosamine (1.65 g, total molar yield 22%, 97.99%).

[0094] The reactions of Examples 1-7 were compared, as shown in Table 1.

[0095] Table 1

[0096] As shown in the table above, different methylation systems and reaction temperatures significantly affect the yield of the final target compound. The optimal yield can be obtained by selecting the formaldehyde-water-sodium cyanoborohydride reaction system as the methylation system and the reaction temperature of 50-70℃.

[0097] In summary, the synthesis method for dabavancin demethyl B2 nitrosamine provided by this invention overcomes the shortcomings of existing synthesis methods and proposes for the first time a method for preparing dabavancin demethyl B2 nitrosamine compound. This method can yield dabavancin demethyl B2 nitrosamine compound with high purity. Subsequently, the high-purity dabavancin demethyl B2 nitrosamine compound can be used as a reference standard for detecting dabavancin demethyl B2 nitrosamine impurities, thereby enabling monitoring of the dabavancin demethyl B2 nitrosamine content.

[0098] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent modifications made based on the content of the present invention specification and drawings, or direct or indirect applications in related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for synthesizing dapavancin demethyl β2-nitrosamine, characterized in that, Includes the following steps: S1: Using dapavancin precursor A-40926-B0 as a raw material, a methylation reaction was carried out to obtain intermediate I; S2: The intermediate I is protected by esterification to obtain intermediate II; S3: The intermediate II is condensed with 3-methylaminopropylamine to obtain intermediate III, and then intermediate IV is obtained by alkaline hydrolysis; S4: Nitrosify the intermediate IV with a nitrosating agent to obtain dabavancin demethyl B2 nitrosamine; The structural formula of A-40926-B0 is shown in Formula (1), the structural formula of intermediate I is shown in Formula (2), the structural formula of intermediate II is shown in Formula (3), the structural formula of intermediate III is shown in Formula (4), the structural formula of intermediate IV is shown in Formula (5), and the structural formula of Bavancin demethyl B2 nitrosamine is shown in Formula (6). Equation (1); Equation (2); Equation (3); Equation (4); Equation (5); Equation (6).

2. The method for synthesizing dapavancin demethyl B2 nitrosamine according to claim 1, characterized in that, The specific steps of S1 are as follows: A-40926-B0 is dissolved in a solvent and then a methylating agent is added to react. After the reaction is complete, intermediate I is obtained.

3. The method for synthesizing dapavancin demethyl β2-nitrosamine according to claim 2, characterized in that, The methylating agent of S1 is selected from one or more of iodomethane, bromomethane, dimethyl sulfate, formaldehyde, and paraformaldehyde.

4. The method for synthesizing dapavancin demethyl B2 nitrosamine according to claim 3, characterized in that, When the methylating agent of S1 is one or more of iodomethane, bromomethane and dimethyl sulfate, an alkali is added during the reaction of S1.

5. The method for synthesizing dapavancin demethyl β2-nitrosamine according to claim 3, characterized in that, When the methylating agent of S1 is formaldehyde and / or paraformaldehyde, a reducing agent, or a reducing agent and an acid, are added during the reaction of S1.

6. The method for synthesizing dapavancin demethyl B2 nitrosamine according to claim 2, characterized in that, The solvent in S1 is selected from one or more of methanol, ethanol, DMF, acetone, and dichloromethane.

7. The method for synthesizing dapavancin demethyl B2 nitrosamine according to claim 1, characterized in that, The specific steps of S2 are as follows: intermediate I is added to isopropanol, sulfuric acid is added to react, and intermediate II is obtained.

8. The method for synthesizing dapavancin demethyl B2 nitrosamine according to claim 1, characterized in that, The specific steps of S3 are as follows: after dissolving intermediate II in a solvent, TBTU, HOBT and 3-methylaminopropylamine are added to react and intermediate III reaction solution is obtained; alkali is added to intermediate III reaction solution to perform hydrolysis and intermediate IV is obtained.

9. The method for synthesizing dapavancin demethyl β2-nitrosamine according to claim 1, characterized in that, The specific steps of S4 are as follows: dissolve intermediate IV in a solvent, add a nitrosating agent, and then adjust the pH of the solution to 2-4 to carry out the reaction to obtain dabavancin demethyl B2 nitrosamine.

10. The method for synthesizing dapavancin demethyl B2 nitrosamine according to claim 9, characterized in that, The nitrosating agent is sodium nitrite.

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