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CN-122011120-A - Method for preparing nitrosamine compound

CN122011120ACN 122011120 ACN122011120 ACN 122011120ACN-122011120-A

Abstract

The invention relates to the technical field of medicine preparation, in particular to a method for preparing a nitrosamine compound. The method comprises the following steps of S1, carrying out esterification protection by taking a dalbavancin precursor A-40926-B0 as a raw material to obtain an intermediate I, S2, carrying out condensation reaction on the intermediate I and 3-methylaminopropylamine to obtain an intermediate II, then carrying out alkaline hydrolysis to obtain an intermediate III, S3, protecting secondary amine on a parent nucleus by the intermediate III through a protective reagent to obtain an intermediate IV, S4, carrying out nitrosation on the intermediate IV through a nitrosation reagent to obtain an intermediate V, S5, carrying out deprotection on the intermediate V to obtain dalbavancin normethyl B0 nitrosamine, and obtaining a product with high purity, wherein a reference substance can be provided for quality control of dalbavancin, and important guiding significance is provided for safe medication.

Inventors

  • GAO HONGLIANG
  • WU YUBIN
  • Lin xinglong
  • CHEN XINYAO
  • ZHANG HONGKUAN
  • LUO XIAOFANG
  • WEI HUA

Assignees

  • 丽珠集团福州福兴医药有限公司

Dates

Publication Date
20260512
Application Date
20260130

Claims (10)

  1. 1. A process for preparing a nitrosamine compound, characterized by comprising the steps of: S1, using a dalbavancin precursor A-40926-B0 as a raw material to perform esterification protection to obtain an intermediate I; s2, carrying out condensation reaction on the intermediate I and 3-methylaminopropylamine to obtain an intermediate II, and then carrying out alkaline hydrolysis to obtain an intermediate III; s3, protecting secondary amine on a parent nucleus by the intermediate III through a protecting reagent to obtain an intermediate IV; s4, nitrosation is carried out on the intermediate IV through a nitrosation reagent to obtain an intermediate V; s5, deprotection of the intermediate V to obtain dalbavancin demethyl B0 nitrosamine; The structural formula of the dapagliflozin precursor 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), the structural formula of the intermediate V is shown in a formula (6), and the structural formula of the bavancin demethyl B0 nitrosamine is shown in a formula (7); formula (1); formula (2); Formula (3); Formula (4); formula (5); formula (6); Formula (7).
  2. 2. The method for preparing the nitrosamine compound according to claim 1, wherein said specific step of S3 is to dissolve said intermediate III with solvent, and add a protecting reagent and alkali for reaction to obtain intermediate IV.
  3. 3. The method for preparing a nitrosamine compound according to claim 2, wherein said protecting agent in S3 comprises one or more of Fmoc-Cl, fmoc-OSu, fmoc-OTCP, fmoc-N 3 , cbz-Cl, alloc-Cl; the alkali in the S3 is selected from one or more of pyridine, triethylamine, DIPEA, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate and dipotassium hydrogen phosphate.
  4. 4. The method for producing a nitrosamine compound according to claim 2, wherein the reaction temperature in S3 is 0-30 ℃.
  5. 5. The method for preparing a nitrosamine compound according to claim 2, characterized in that the molar ratio of the protecting agent in S3 to the darbavancin precursor a-40926-B0 is (0.5:1) to (1:1).
  6. 6. The method for preparing the nitrosamine compound according to claim 1, characterized in that said specific step of S5 is to dissolve intermediate V with solvent, add deprotection reagent to react, and get the final product of bavancin demethyl B0 nitrosamine.
  7. 7. The method for producing a nitrosamine compound according to claim 6, wherein said deprotection reagent in S5 is one or more selected from piperidine, diethylamine, dimethylamine, morpholine, DIPEA, pd (PPh 3 ) 4 -morpholine, pd/C-ammonium formate).
  8. 8. The method for preparing the nitrosamine compound according to claim 1, wherein said specific step of S1 is to add said dapagliflozin precursor A-40926-B0 into isopropanol, and add sulfuric acid for reaction, to obtain intermediate I.
  9. 9. The method for preparing the nitrosamine compound according to claim 1, characterized in that the specific step of S2 is that after dissolving the intermediate I with a solvent, adding TBTU, HOBT and 3-methylaminopropylamine for reaction to obtain intermediate II reaction solution, adding alkali into the intermediate II reaction solution for hydrolysis to obtain intermediate III.
  10. 10. The method for preparing the nitrosamine compound according to claim 1, characterized in that the specific step of S4 is that intermediate IV is dissolved by solvent, nitrosating reagent is added, then pH is adjusted to 2-4 for reaction, and intermediate V is obtained.

Description

Method for preparing nitrosamine compound Technical Field The invention relates to the technical field of medicine preparation, in particular to a method for preparing a nitrosamine compound. Background Dapagliflozin is a semisynthetic glycopeptide antibiotic, exerts its bactericidal effect by disrupting cell wall biosynthesis, and becomes an antibacterial drug for administration of drugs in clinical practice for a few weeks. CN109467592B describes the preparation process of dapagliflozin, which comprises the steps of carrying out amidation condensation, deprotection and hydrolysis on 3-dimethylaminopropylamine and a mother nucleus in sequence after esterification protection of a precursor A-40926 of dapagliflozin to obtain the final product. Nitrosamine impurities belong to the "queue of interest" substances mentioned in the ICH M7 (R2) guidelines for assessing and controlling DNA-reactive (mutagenic) impurities in drugs to limit potential carcinogenic risk, are genotoxic substances for certain animals, some of which have been listed by the International agency for research on cancer (IARC) as possible or potential human carcinogens. The national drug administration drug audit center issues the technical guidelines (trial runs) for the study of nitrosamine impurities in chemical drugs, and proposes that the control of nitrosamine impurities in drugs should be based on the requirement of ICH M7 (R1) so as to make the level of the impurities in bulk drugs and preparations lower than acceptable limits. The FDA releases the 18 th revision of Recommended Acceptable INTAKE LIMITS for Nitrosamine Drug Substance-Related Impurities (NDSRIs), further enhancing the supervision of nitrosamine impurities in pharmaceuticals. 9 dapagliflozin derivatives nitrosamines are indicated in the guideline, and the acceptable uptake limit for dapagliflozin normethyl B0 nitrosamines is specified to be 1500 ng/day. In view of this, the present invention has been made in order to control the content of dalbavancin norb 0 nitrosamine in a dalbavancin drug substance or formulation to a low level that meets safety requirements. Disclosure of Invention The invention aims to solve the technical problem of providing a method for preparing a nitrosamine compound, which is used for providing an impurity reference substance during quality control. In order to solve the technical problems, the technical scheme adopted by the invention is that the method for preparing the nitrosamine compound comprises the following steps: S1, using a dalbavancin precursor A-40926-B0 as a raw material to perform esterification protection to obtain an intermediate I; s2, carrying out condensation reaction on the intermediate I and 3-methylaminopropylamine to obtain an intermediate II, and then carrying out alkaline hydrolysis to obtain an intermediate III; s3, protecting secondary amine on a parent nucleus by the intermediate III through a protecting reagent to obtain an intermediate IV; s4, nitrosation is carried out on the intermediate IV through a nitrosation reagent to obtain an intermediate V; s5, deprotection of the intermediate V to obtain dalbavancin demethyl B0 nitrosamine; The structural formula of the dapagliflozin precursor 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), the structural formula of the intermediate V is shown in a formula (6), and the structural formula of the bavancin demethyl B0 nitrosamine is shown in a formula (7); formula (1); formula (2); Formula (3); Formula (4); formula (5); formula (6); Formula (7). The method has the beneficial effects that the precursor compound for synthesizing the dalbavancin demethyl B0 nitrosamine has complex structure, sensitive groups exist, the reaction process has a plurality of impurities, the purification is difficult and other technical difficulties, and no synthesis method of the dalbavancin demethyl B0 nitrosamine is reported at present. The invention provides a method for preparing the dalbavancin demethyl B0 nitrosamine compound, which has high product purity, can provide a reference substance for quality control of dalbavancin, and provides important guiding significance for safe medication. Drawings FIG. 1 is a hydrogen spectrum of dalbavancin norB 0 nitrosamine in an embodiment of the invention; FIG. 2 is a graph of the carbon spectrum of dalbavancin norB 0 nitrosamine in an embodiment of the invention; FIG. 3 is a mass spectrum of dalbavancin norB 0 nitrosamine in an embodiment of the invention; FIG. 4 is an infrared spectrum of dalbavancin norB 0 nitrosamine in an embodiment of the invention. Detailed Description In order to describe the technical contents, the achieved objects and effects of the present inve