CN-119462412-B - C11a-OH tetracycline compound and synthesis method thereof

Abstract

The invention provides a synthesis method of a C11a-OH tetracycline compound, which comprises the following steps of sequentially adding a polar solvent and a tetracycline raw material (1) into a round-bottomed flask, slowly adding m-chloroperoxybenzoic acid into the round-bottomed flask at room temperature after stirring, reacting for 2 hours, decompressing and spirally evaporating the solvent, and preparing the target C11a-OH tetracycline compound (2) through reversed phase, wherein the reaction formula is shown as a formula (II) . The synthesis method of the C11a-OH tetracycline compound is simple and efficient, has a wide application range, and is easy for large-scale production.

Inventors

• Chen Juanlou
• YANG WEIXING
• PENG GUANGRONG
• CHEN GANG
• WU HE

Assignees

• 盐城市大丰区天生联合药业有限公司
• 上海交通大学

Dates

Publication Date

20260512

Application Date

20240830

Claims (8)

1. 1. A method for synthesizing a C11a-OH tetracycline compound, comprising the steps of: Sequentially adding a polar solvent and a tetracycline raw material (1) into a round-bottomed flask, stirring, slowly adding m-chloroperoxybenzoic acid into the mixture at room temperature for reaction 2. After hours, the solvent is distilled off under reduced pressure, and the target C11a-OH tetracycline compound (2) is obtained after reverse phase preparation, the reaction formula is shown as the formula (II) , (II) Wherein: R1 is hydrogen or amido; r2 is hydrogen, halogen or dimethylamino; r3, R4 and R5 are hydrogen or hydroxyl.
2. 2. The method for synthesizing a C11a-OH tetracycline compound of claim 1, wherein said polar solvent is an ether and water.
3. 3. The method for synthesizing a C11a-OH tetracycline compound of claim 2, wherein said ether is tetrahydrofuran.
4. 4. The method for synthesizing a C11a-OH tetracycline compound of claim 1, further comprising a lewis acid.
5. 5. The method for synthesizing a C11a-OH tetracycline compound of claim 4, wherein said Lewis acid is boron trifluoride Diethyl ether or boron trifluoride acetic acid.
6. 6. The method for synthesizing a C11a-OH tetracycline compound of claim 4, wherein said tetracycline starting material (1) and said via The molar ratio of the easily-si acid is 1:0-1:6.
7. 7. The method for synthesizing a C11a-OH tetracycline compound of claim 1, wherein said tetracycline starting material (1) and meta The molar ratio of the chloroperoxybenzoic acid is 1:1-1:4.
8. 8. The method for synthesizing a C11a-OH tetracycline compound of claim 1, wherein acetonitrile is used in the reverse phase preparation The volume ratio of 0.8% formic acid or methanol to 0.8% formic acid and water is gradually changed from 1:19 to 1:3.

Description

C11a-OH tetracycline compound and synthesis method thereof Technical Field The invention relates to the field of chemical industry, in particular to a C11a-OH tetracycline compound and a synthesis method thereof. Background Tetracyclines are a broad-spectrum antibiotic and have good inhibition ability on various bacteria and fungi including gram-positive bacteria, gram-negative bacteria and anaerobic bacteria. Studies show that the antibacterial mechanism of the tetracycline is coordinated with magnesium ions, and O11 and O12 of the tetracycline are combined with ribose through the magnesium ions, so that the inhibition effect is achieved. Only through a biosynthesis method, the C11a position of the tetracycline generates hydroxyl so as to prevent the hydroxyl from coordinating with magnesium ions, so that the tetracycline is decomposed, and the bacterial drug resistance is caused. There is no disclosure of the general structural formula of the related tetracycline compound having a hydroxyl group at the C11a position and its chemical synthesis method. Therefore, it is necessary to provide a new technical solution. Disclosure of Invention In order to solve the technical problems in the prior art, the invention discloses a synthesis method of a C11a-OH tetracycline compound, which comprises the following specific technical scheme: The invention provides a synthesis method of a C11a-OH tetracycline compound, which comprises the following steps: Sequentially adding a polar solvent and a tetracycline raw material (1) into a round-bottom flask, stirring, slowly adding m-chloroperoxybenzoic acid into the flask at room temperature, reacting for 2 hours, decompressing, rotationally evaporating the solvent, and preparing the target C11a-OH tetracycline compound (2) through reverse phase preparation, wherein the reaction formula is shown as the formula (II) , (II) Wherein: R1 is hydrogen or amido; r2 is hydrogen, halogen or dimethylamino; r3, R4 and R5 are hydrogen or hydroxyl. Further, the polar solvent is ethers and water. Further, the ether is tetrahydrofuran. Further, a lewis acid is also included. Further, the Lewis acid is boron trifluoride diethyl ether or boron trifluoride acetic acid. Further, the molar ratio of the tetracycline raw material (1) to the Lewis acid is 1:0-1:6. Further, the molar ratio of the tetracycline raw material (1) to the m-chloroperoxybenzoic acid is 1:1-1:4. Further, during the reverse phase preparation, the volume ratio of acetonitrile or methanol+0.8% formic acid to water is gradually changed from 1:19 to 1:3. The invention has the following beneficial effects: 1. The C11a-OH tetracycline compound provided by the invention belongs to a finished product obtained by a chemical synthesis method for the first time, and discloses a general structural formula and chemical properties corresponding to the compound, which can be applied to the research of bacterial drug resistance mechanism and the research of further degradation products. 2. The synthesis method of the C11a-OH tetracycline compound provided by the invention is simple and efficient, has a wide application range, and is easy for large-scale production. Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Detailed Description Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to like or similar elements or elements having like or similar functions throughout. The embodiments described below by referring to the drawings are illustrative and intended to explain the present invention and should not be construed as limiting the invention. In the description of the present invention, it should be understood that the directions or positional relationships indicated by the terms "upper", "lower", "top", "bottom", "inner", "outer", etc. are based on the directions or positional relationships shown in the drawings, are merely for convenience of describing the present invention and simplifying the description, and do not indicate or imply that the apparatus or elements referred to must have a specific orientation, be constructed and operated in a specific orientation, and thus should not be construed as limiting the present invention. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise. In the present invention, unless explicitly specified and limited otherwise, the terms "mounted," "connected," "secured," and the like are to be construed broadly, and may be, for example, fixedly connected, detachably connected, or integrally formed, mechanically connected, electrically connected, directly connected, indirectly connected via an intervening medium, or in communication between two eleme