阅读说明：本技术 一种阿维巴坦中间体的制备方法 (Preparation method of avibactam intermediate ) 是由 龚杰 谢永居 张应军 周忠波 余翔 曹敏 张惠芝 于 2019-09-05 设计创作，主要内容包括：本发明公开了一种阿维巴坦中间体的制备方法,化合物I与三甲基碘化亚砜在碱的存在下反应制备得到化合物II；所述化合物I、化合物II结构如下：R为甲基、乙基、苄基、叔丁基、烯丙基中一种；所述的碱为氢氧化镁、氢氧化锂、氢氧化钙中一种或多种。本发明的阿维巴坦中间体的制备方法,该方法以带有双保护的焦谷氨酸酯为原料,在碱的存在下与三甲基碘化亚砜反应得到阿维巴坦中间体,该方法避免了原有技术中强碱存在的安全隐患,反应条件要求苛刻,工艺控制要求严格等缺点,该方法反应条件温和,操作简单,安全性高,反应杂质少等优点。(The invention discloses a preparation method of an avibactam intermediate, wherein a compound I and trimethyl sulfoxide iodide react in the presence of alkali to prepare a compound II; the structures of the compound I and the compound II are as follows: r is one of methyl, ethyl, benzyl, tertiary butyl and allyl; the alkali is one or more of magnesium hydroxide, lithium hydroxide and calcium hydroxide. The preparation method of the avibactam intermediate uses pyroglutamic acid ester with double protection as a raw material to react with trimethyl sulfoxide iodide in the presence of alkali to obtain the avibactam intermediate, avoids the defects of potential safety hazard, strict reaction condition requirement, strict process control requirement and the like of strong alkali in the prior art, and has the advantages of mild reaction condition, simple operation, high safety, less reaction impurities and the like.)

1. A preparation method of an avibactam intermediate is characterized in that a compound I and trimethyl sulfoxide iodide react in the presence of alkali to prepare a compound II;

the structures of the compound I and the compound II are as follows:

r is one of methyl, ethyl, benzyl, tertiary butyl and allyl;

the alkali is one or more of magnesium hydroxide, lithium hydroxide and calcium hydroxide.

2. The preparation method of the avibactam intermediate according to claim 1, wherein the reaction temperature is 20-40 ℃.

3. The preparation method of the avibactam intermediate according to claim 1, wherein the reaction time is 1-3 hours.

4. The preparation method of the avibactam intermediate according to claim 1, wherein the molar ratio of the compound I to the base is 1 (1-2).

5. The preparation method of the avibactam intermediate according to claim 1, wherein the molar ratio of the compound I to the trimethyl sulfoxide iodide is 1 (1-3).

6. The method for preparing the avibactam intermediate according to claim 1, wherein the solvent is one or more of dimethyl sulfoxide, dimethylformamide and dioxane.

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an avibactam intermediate.

Background

Abamebactam (avibactam) is a novel beta-lactamase inhibitor with a non-beta-lactam structure, and is combined with a broad-spectrum cephalosporin ceftazidime (ceftazidime) to treat complex intraperitoneal infection (cIAI) and complex urinary tract infection (cUTI), and the combination is approved by FDA at present and sold on the market under the name of Avycaz. Combinations with other antibiotics (e.g., ceftaroline fosamil, thiaximo monoamides, etc.) are under clinical investigation. Compared with 3 beta-lactamase inhibitors on the market, clavulanic acid, sulbactam and tazobactam, the abamectin has stronger effect and wider range, and has obvious inhibition effect on A, C and part D beta-lactamase.

The abamectin has a diazabicyclooctane framework, has a structure different from that of a classical beta-lactamase inhibitor, can be recovered by reverse reaction, and has a long-acting enzyme inhibition effect. In addition, the classical beta-lactamase inhibitor has no or weak inhibition effect on C-class enzyme, but the abamectin has obvious effect of inhibiting the C-class enzyme and wider enzyme inhibition spectrum. Abamebactam is clinically applied in the form of sodium salt, the chemical name of the Abamebactam is sulfuric acid mono [ (1R,2S,5R) -2-aminocarbonyl-7-oxo-1, 6-azabicyclo [3.2.1] oct-6-yl ester sodium salt, and the specific structure is as follows:

there are many reports on the synthesis of avibactam, such as CN103649051B, CN106699756A, US2012323010A1, EP2657234A1, etc. All use strong bases such as sodium hydrogen, potassium tert-butoxide and the like, have high requirements on reaction moisture, need dehydration treatment of a solvent, difficult process control and more reaction impurities.

Patent document CN 108822014 a discloses a method for synthesizing an avibactam intermediate, which uses carbonate as alkali to perform reaction, but the carbonate is weak in alkalinity, so the reaction time is long, the use amount of the alkali is high, the post-treatment is complicated, and the preparation cost is high. In addition, when carbonate is used as alkali for reaction, bubbles which are difficult to control are easily generated during industrial scale-up experiments, the safety of the industrial process is reduced, and the post-treatment difficulty is increased.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a preparation method of an avibactam intermediate. The method has the advantages of mild conditions, high safety, simple operation, high reaction purity, less impurities and easy industrial production.

A preparation method of an avibactam intermediate comprises the steps of reacting a compound I with trimethyl sulfoxide iodide in the presence of alkali to prepare a compound II;

the structures of the compound I and the compound II are as follows:

r is one of methyl, ethyl, benzyl, tertiary butyl and allyl; further preferred is an ethyl group or a benzyl group.

The alkali is one or more of magnesium hydroxide, lithium hydroxide and calcium hydroxide. More preferably, magnesium hydroxide or lithium hydroxide. When the alkali is used for reaction, the byproduct is water, the reaction temperature can be directly room temperature or the temperature close to room temperature, and the reaction time is short.

Preferably, the reaction temperature is 20 to 40 ℃. Further preferably 25 to 35 ℃.

Preferably, the reaction time is 1 to 3 hours.

Preferably, the molar ratio of the compound I to the base is 1 (1-2). Further preferably 1 (1-1.5).

Preferably, the molar ratio of the compound I to the trimethyl sulfoxide iodide is 1 (1-3). Further preferably 1 (1-1.5).

Preferably, the solvent is one of dimethyl sulfoxide, dimethylformamide and dioxane.

Compared with the prior art, the invention has the beneficial effects that:

the invention discloses a preparation method of an avibactam intermediate, which takes pyroglutamic acid ester with double protection as a raw material to react with trimethyl sulfoxide iodide in the presence of alkali to obtain the avibactam intermediate.

Detailed Description