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CN-121974984-A - Synthesis method of dalbavancin demethyl B2 nitrosamine

CN121974984ACN 121974984 ACN121974984 ACN 121974984ACN-121974984-A

Abstract

The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing dalbavancin demethyl B2 nitrosamine. The synthesis method comprises the following steps of S1, carrying out methylation reaction by taking a daphnetin precursor A-40926-B0 as a raw material to obtain an intermediate I, S2, carrying out 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 then carrying out alkaline hydrolysis to obtain an intermediate IV, S4, carrying out nitrosation on the intermediate IV by a nitrosation reagent to obtain the up-to-the-balwanin demethyl B2 nitrosamine, and the synthesis method has high reaction yield, and can obtain the up-to-the-balwanin demethyl B2 nitrosamine compound with high purity and provide a reference substance for quality control of the daphnetin.

Inventors

  • CHEN XINYAO
  • GAO HONGLIANG
  • ZHANG HONGKUAN
  • Lin xinglong
  • HUANG HUILING
  • LU ZHENXIN

Assignees

  • 丽珠集团福州福兴医药有限公司

Dates

Publication Date
20260505
Application Date
20260129

Claims (10)

  1. 1. The synthesis method of the dalbavancin demethyl B2 nitrosamine is characterized by comprising the following steps of: s1, taking a dalbavancin precursor A-40926-B0 as a raw material, and performing 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 then carrying out alkaline hydrolysis to obtain an intermediate IV; S4, nitrosation is carried out on the intermediate IV through a nitrosation reagent, so as to obtain the final product of the bavancin demethyl B2 nitrosamine; The structural formula of the A-40926-B0 is shown in a formula (1), the structural formula of the intermediate I is shown in a formula (2), the structural formula of the intermediate II is shown in a formula (3), the structural formula of the intermediate III is shown in a formula (4), the structural formula of the intermediate IV is shown in a formula (5), and the structural formula of the bavancin demethyl B2 nitrosamine is shown in a formula (6); Formula (1); formula (2); Formula (3); Formula (4); Formula (5); Formula (6).
  2. 2. The method for synthesizing dalbavancin norB 2 nitrosamine as claimed in claim 1, wherein said S1 comprises the specific steps of dissolving said A-40926-B0 in a solvent, adding a methylating agent for reaction, and obtaining intermediate I after the reaction is completed.
  3. 3. The method for synthesizing dalbavancin normethyl B2 nitrosamine as claimed in claim 2, wherein said methylation reagent of S1 is one or more selected from methyl iodide, methyl bromide, dimethyl sulfate, formaldehyde and paraformaldehyde.
  4. 4. The method for synthesizing dalbavancin norb 2 nitrosamine according to claim 3, wherein when said methylation reagent of S1 is one or more of methyl iodide, methyl bromide and dimethyl sulfate, a base is added during the reaction of S1.
  5. 5. A method of synthesizing dalbavancin norb 2 nitrosamine according to claim 3, characterized in that when said methylation reagent of S1 is formaldehyde and/or paraformaldehyde, said S1 is reacted with addition of a reducing agent, or a reducing agent and an acid.
  6. 6. The method for synthesizing dalbavancin norb 2 nitrosamine according to claim 2, wherein said solvent in S1 is one or more selected from methanol, ethanol, DMF, acetone, and dichloromethane.
  7. 7. The method for synthesizing dalbavancin norB 2 nitrosamine as claimed in claim 1, wherein said S2 comprises the specific steps of adding said intermediate I into isopropanol, adding sulfuric acid for reaction, and obtaining intermediate II.
  8. 8. The method for synthesizing dalbavancin norB 2 nitrosamine according to claim 1, characterized by comprising the specific steps of dissolving said intermediate II with a solvent, adding TBTU, HOBT and 3-methylaminopropylamine for reaction to obtain intermediate III reaction solution, adding alkali into said intermediate III reaction solution, and hydrolyzing to obtain intermediate IV.
  9. 9. The method for synthesizing the dalbavancin norb 2 nitrosamine according to claim 1, characterized by comprising the specific steps of dissolving an intermediate IV with a solvent, adding a nitrosation reagent, and then adjusting the pH of the solution to 2-4 for reaction to obtain the dalbavancin norb 2 nitrosamine.
  10. 10. The method for synthesizing dalbavancin norb 2 nitrosamine as claimed in claim 9, wherein said nitrosating agent is sodium nitrite.

Description

Synthesis method of dalbavancin demethyl B2 nitrosamine Technical Field The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing dalbavancin demethyl B2 nitrosamine. Background The dapagliflozin is also called as a channel Gu Meisu, is a long-acting semisynthetic lipopeptide glycopeptide antibiotic, has an in vivo half-life reaching 149-250 h, and plays an important role in treating acute bacterial skin and skin structure infection due to unique long-acting property and strong drug resistance gram positive bacteria activity. A plurality of preparation patents of the dapagliflozin exist at present, namely, WO2022148868A1 and CN109467592B are prepared by carrying out protective esterification on a precursor A-40926 of the dapagliflozin, carrying out amidation condensation and deprotection hydrolysis on 3-dimethylaminopropylamine and a mother nucleus to obtain the dapagliflozin. Genotoxic impurities refer to compounds that can directly or indirectly damage DNA, cause genetic mutations or are carcinogenic, whereas imine impurities are typical genotoxic impurities. Nitrosamine impurities with high carcinogenicity have attracted common attention by global regulatory authorities. Nitrosamine impurities belong to the "queue of interest" substance mentioned in the international pharmaceutical registration technology coordination meeting ICH M7 (R1) ((assessment and control of DNA-reactive (mutagenic) impurities in drugs to limit potential carcinogenic risk) [1 ]) guidelines, which at very low doses (typically nanograms) can significantly increase the risk of cancer and are therefore individually classified as the highest risk level. The Chinese national drug administration drug audit center issues the technical guidelines (trial) for researching nitrosamine impurities in chemical drugs, and proposes that the control of nitrosamine impurities in drugs should be based on meeting ICH M7 (R1) requirements, so that the level of the impurities in bulk drugs and preparations is lower than acceptable limit. Meanwhile, FDA issued "Recommended Acceptable INTAKE LIMITS for Nitrosamine Drug Substance-Related Impurities (NDSRIs)," enhanced the supervision of nitrosamine impurities in all approved and on-going drugs, the guidance guidelines pointed out 9 dalbavancin derivative nitrosamine impurities, dalbavancin norb 2 nitrosamine belonging to one of these 9 nitrosamine impurities, which clearly specifies that the acceptable uptake limit of dalbavancin norb 2 nitrosamine is 1500 ng/day, see table below: Therefore, the accurate detection of the dalbavancin demethyl B2 nitrosamine in the dalbavancin has important practical significance for quality detection and quality control of the dalbavancin. The dalbavancin demethyl B2 nitrosamine belongs to one of dalba Mo Xingya nitrosamine impurities, and no synthesis method of dalbavancin demethyl B2 nitrosamine is reported at present. The precursor compound for synthesizing the dalbavancin demethyl B2 nitrosamine has complex structure, sensitive groups, more impurities, difficult purification and other technical difficulties in the reaction process, so that a reference substance meeting the regulations cannot be provided for the quality control research of the impurities at present. Disclosure of Invention The invention aims to provide a synthesis method of dalbavancin demethyl B2 nitrosamine, which is used for providing an impurity reference substance in quality control. In order to solve the technical problems, the technical scheme adopted by the invention is that the synthesis method of the dalbavancin demethyl B2 nitrosamine comprises the following steps: s1, taking a dalbavancin precursor A-40926-B0 as a raw material, and performing 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 then carrying out alkaline hydrolysis to obtain an intermediate IV; S4, nitrosation is carried out on the intermediate IV through a nitrosation reagent, so as to obtain the final product of the bavancin demethyl B2 nitrosamine; The structural formula of the A-40926-B0 is shown in a formula (1), the structural formula of the intermediate I is shown in a formula (2), the structural formula of the intermediate II is shown in a formula (3), the structural formula of the intermediate III is shown in a formula (4), the structural formula of the intermediate IV is shown in a formula (5), and the structural formula of the bavancin demethyl B2 nitrosamine is shown in a formula (6); Formula (1); formula (2); Formula (3); Formula (4); Formula (5); Formula (6). The synthesis method has the beneficial effects that the synthesis method has high reaction yield, can obtain the desmethyl B2 nitrosamine compound with purity up to the purity of the bav