Process for the preparation of an avibactam intermediate

Abstract

The application belongs to the field of compound synthesis and provides a preparation method of an avibactam intermediate. In a protective atmosphere, isopropyl alcohol and an oxidizing agent are mixed, then an ammonia source is added, an oxidation addition reaction is carried out, then a solvent, an alkaline substance and a benzyl halide are sequentially added, a substitution reaction is carried out, then an acidic substance is added, and the avibactam intermediate is prepared; the benzyl halide is added at 40-60 DEG C; the temperature of the substitution reaction is 40-60 DEG C, and / or the time of the substitution reaction is 1-3 h. The method greatly reduces the generation of three wastes, reduces the loss of reaction raw materials, can improve the comprehensive yield of OBH01 to more than 93%, has short reaction time, and can respectively complete the oxidation addition reaction and the substitution reaction within 3 h, and finally has high yield and purity of the OBH product, and good reaction stability.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and more specifically, to a method for preparing an avibactam intermediate. Background Technology

[0002] Avibactam (NXL-104) belongs to the diazabicyclic octanone class of compounds (Chinese name: sodium salt of mono[(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-azabicyclic[3.2.1]oct-6-yl] ester). Avibactam is a highly effective non-β-lactam inhibitor. While it does not possess significant antibacterial activity itself, it inhibits type A (including extended-spectrum β-lactamases ESBL and carbapenemase KPC) and type C β-lactamases, and has wide applications in the pharmaceutical field. The structure of avibactam is shown in formula (II) below:

[0003]

[0004] In the process of preparing avibactam sodium, the synthesis of avibactam intermediates is involved. Among them, the preparation method of OBH intermediate (chemical name benzyloxyamine hydrochloride, CAS number: 2687-43-6) is generally obtained by reacting 2,3-dihydro-4H-[1]benzothiapyrimidine-4-one and methanol under alkaline conditions for more than 16 hours, and then by acid hydrolysis and salt formation. The by-products are difficult to remove, the single-step reaction takes too long (each step takes at least 16 hours, and the total reaction time exceeds 20 hours), and the yield is low (generally 20-30%).

[0005] Therefore, there is an urgent need to develop a method for preparing avibactam intermediate (OBH intermediate) with high yield, maximizing the utilization of raw materials, and shortening the reaction time. Summary of the Invention

[0006] This invention aims to solve at least one of the technical problems existing in the prior art. To this end, this invention proposes a method for preparing avibactam intermediates. The method of this invention has a short reaction time (single-step reaction not exceeding 3 hours), high yield, high product purity (yield reaching 81.2-85%, purity reaching 99.5-99.92%), good reaction stability, low production cost, suitability for industrial production, easy product separation and purification, simple and safe operation, low production waste and simple treatment, and is green and efficient.

[0007] The first aspect of the present invention provides a method for preparing an avibactam intermediate.

[0008] Specifically, a method for preparing an avibactam intermediate includes the following steps:

[0009] In a protective atmosphere, isopropanol and an oxidant are first mixed, then an ammonia source is added to carry out an oxidative addition reaction. A solvent, a basic substance, and benzyl halide are then added sequentially to carry out a substitution reaction. An acidic substance is then added to react with the avibactam intermediate. Benzyl halide is added at 40-60°C. The substitution reaction temperature is 40-60°C, and / or the substitution reaction time is 1-3 hours.

[0010] The structure of the avibactam intermediate is shown in formula (Ⅰ):

[0011]

[0012] This invention utilizes isopropanol (CAS: 67-63-0) as the reactant, sequentially adding an oxidant and an ammonia source to initiate an oxidative addition reaction. Then, a solvent, a basic substance, and benzyl halide are added for a substitution reaction. Finally, an acidic substance is added to hydrolyze the product into a salt, yielding the avibactam intermediate OBH. Because this invention designs the reaction route, the entire preparation process can be completed in a single pot, avoiding the separation of intermediate products and directly obtaining the final product. Furthermore, the addition of benzyl halide ensures the formation of OBH01 (2-Propanone, O-(phenylmethyl)oxime), and the addition of an acidic substance to hydrolyze the oxime reduces impurity formation, minimizes product loss due to washing and extraction steps, and eliminates unnecessary separation steps, ensuring high purity and high yield. The acidic conditions also promote rapid reaction, ensuring a fast reaction rate and shortening the reaction time.

[0013] Preferably, the oxidant is sodium hypochlorite.

[0014] Preferably, the ammonia source is NH3.

[0015] Preferably, the isopropanol and oxidant are mixed at 5-15°C, wherein the oxidant is added dropwise to the isopropanol for 0.5-1.5 hours, and then an ammonia source is added, and the temperature is raised to 30-50°C for an oxidative addition reaction for 0.5-2 hours.

[0016] Preferably, the mass ratio of isopropanol, benzyl halide, acidic substance, and alkaline substance is 1:(1-2.0):(2-3.0):(0.1-1.0).

[0017] More preferably, the mass ratio of isopropanol, benzyl halide, acidic substance, and alkaline substance is 1:(1.5-1.9):(2.4-2.8):(0.4-0.75).

[0018] Preferably, before adding the ammonia source, the ammonia source is first dissolved in methanol to obtain a mixed solution of ammonia and methanol (ammonia-methanol), and then mixed with isopropanol and oxidant.

[0019] Preferably, after the oxidative addition reaction, the solvent is removed. The main purpose of removing the solvent is to remove methanol.

[0020] Preferably, after removing the solvent, there is no need to remove the solid; the solvent, alkaline substance, and benzyl halide are directly added to carry out the substitution reaction. This invention employs a one-pot method, eliminating the need to remove the intermediate product midway through the reaction.

[0021] Preferably, the solvent removal method is distillation.

[0022] Preferably, the benzyl halide is added dropwise.

[0023] Preferably, the benzyl halide is at least one of benzyl chloride, benzyl bromide, and benzyl iodide.

[0024] More preferably, the benzyl halide is benzyl chloride (CAS: 100-44-7).

[0025] Preferably, the solvent is methanol and / or acetonitrile.

[0026] More preferably, the solvent is methanol.

[0027] Preferably, the alkaline substance is at least one selected from sodium hydroxide, potassium carbonate, and triethylamine. The alkaline substance provides an alkaline environment, removing the acid generated in the reaction through neutralization and promoting the reaction to proceed.

[0028] More preferably, the alkaline substance is sodium hydroxide.

[0029] Preferably, the acidic substance is hydrochloric acid.

[0030] Preferably, the acidic substance is added at 40-60°C, and after adding the acidic substance, the reaction is maintained at this temperature for 20-40 minutes.

[0031] Preferably, the protective atmosphere is at least one of nitrogen, helium, neon, and argon.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] In this invention, isopropanol and an oxidant are first mixed in a protective atmosphere, followed by the addition of an ammonia source for an oxidative addition reaction. Then, a solvent, a basic substance, and benzyl halide are added, and a substitution reaction is carried out at 40-60°C for 1-3 hours. Finally, an acidic substance is added to obtain the avibactam intermediate. The benzyl halide is added at 40-60°C. This invention differs from previous methods that directly use acetone oxime as a starting material. Instead, isopropanol is used as the starting material, integrating the acetone oxime synthesis process into the substitution reaction. OBH01 is prepared in a one-pot method, eliminating the need to remove the intermediate product during the process. This significantly reduces waste generation and the loss of reaction materials. The overall yield of OBH01 can be increased to over 93%, and the reaction time is short (the oxidative addition reaction and the substitution reaction can each be completed within 3 hours). The final OBH product has high yield and purity, with an overall yield of 81.2-85% and a purity of 99.5-99.92%, exhibiting good reaction stability. Attached Figure Description

[0034] Figure 1 This is a liquid chromatogram of OBH, the avibactam intermediate obtained in Example 1 of the present invention. Detailed Implementation

[0035] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0036] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0037] Example 1

[0038] A method for preparing an avibactam intermediate (OBH) includes the following steps:

[0039] (1) In a nitrogen atmosphere at 30℃, 25.0 kg of isopropanol was pumped into a 2000 L reactor. The temperature was then controlled at 10℃, and 120.0 kg of sodium hypochlorite aqueous solution (10% solute concentration) was added dropwise for 1 hour. Then, 50.0 kg of ammonia-methanol solution was added, the temperature was raised to 40℃, and the reaction was carried out for 1.5 hours. The reaction was controlled until the product content was greater than 98%, and the temperature was controlled at 40℃. Excess methanol and ammonia were removed by distillation under reduced pressure (-0.85 MPa). 98.0 kg of methanol was pumped in, and 14.0 kg of sodium hydroxide was added in batches, stirring until clear. After the internal temperature of the reactor was controlled at 50℃, 46.0 kg of benzyl chloride was added dropwise. The temperature inside the reactor was maintained at 50℃, and the substitution reaction was carried out by stirring for 1.5 hours until the reaction was controlled. After the reaction was controlled, 125.0 kg of water was pumped into the system, the system temperature was lowered to 25℃, and the system was stirred for 10 minutes. The organic phase was drawn back into the reactor, and 34.0 kg of saturated sodium chloride solution was drawn into the reactor. The mixture was stirred for 30 min and allowed to stand for 30 min. Then, vacuum distillation was performed at 30 °C and a vacuum degree of -0.085 to -0.095 MPa to concentrate the solution to an oily state.

[0040] (2) Maintaining the temperature at 30°C, the organic phase was drawn back into the reactor, and warm water at 60°C was introduced into the jacket. When the temperature inside the system rose to 50°C, 64.0 kg of hydrochloric acid was added. After the addition was complete, the mixture was kept warm and stirred for 30 min. After the system temperature dropped to 20°C, crystallization was carried out by stirring for 1 h. The mixture was then discharged into a centrifuge, and the reactor was rinsed with 7.0 kg of methanol. Centrifugation was continued for 0.5 h. The mixture was dried at 50°C with forced air for 12 h until the moisture content in the product was <0.5%, thus obtaining the final product OBH.

[0041] The reaction process in step (1) above is as follows:

[0042]

[0043] The reaction process in step (2) above is as follows:

[0044]

[0045] Example 2

[0046] A method for preparing an avibactam intermediate, differing from Example 1 in that sodium hydroxide in Example 1 is replaced with potassium carbonate, specifically including the following steps:

[0047] (1) In a nitrogen atmosphere at 30℃, 25.0 kg of isopropanol was pumped into a 2000 L reactor, followed by the dropwise addition of 120.0 kg of sodium hypochlorite aqueous solution (solute mass concentration 10%). The reaction was carried out at 10℃ for 1 h. Then, 50.0 kg of ammonia-methanol solution was added, the temperature was raised to 40℃, and the reaction was carried out for 1.5 h. The product content was controlled until it was greater than 98%. The excess methanol and ammonia were removed by distillation under reduced pressure (-0.85 MPa) at 40℃. 98.0 kg of methanol was pumped in, followed by 14 kg of potassium carbonate. The mixture was stirred until clear. The internal temperature of the reactor was controlled at 50℃, and 46.0 kg of benzyl chloride was added dropwise. The temperature inside the reactor was maintained at 50℃, and the mixture was stirred for 1 h until the reaction was completed. After the reaction was completed, 125.0 kg of water was pumped into the system, the system temperature was lowered to 30℃, and the mixture was stirred for 10 min. The organic phase was drawn back into the reactor, and 34.0 kg of saturated sodium chloride solution was drawn into the reactor. The mixture was stirred for 30 min and allowed to stand for 30 min. Then, vacuum distillation was performed at 30 °C and a vacuum degree of -0.085 to -0.095 MPa to concentrate the solution to an oily state.

[0048] (2) Maintaining the temperature at 30°C, the organic phase was drawn back into the reactor. Warm water at 60°C was introduced into the jacket. When the temperature inside the system rose to 50°C, 64.0 kg of hydrochloric acid was added. After the addition was complete, the mixture was kept warm and stirred for 30 min. After the system temperature dropped to 20°C, crystallization was carried out by stirring for 1 h. The mixture was then discharged into a centrifuge. The reactor was rinsed with 7.0 kg of methanol and centrifuged for another 0.5 h. The mixture was dried at 50°C with forced air for 12 h until the moisture content in the product was <0.5%, thus obtaining the final product OBH.

[0049] Example 3

[0050] A method for preparing an avibactam intermediate, differing from Example 1 in that methanol in Example 1 is replaced with acetonitrile, specifically including the following steps:

[0051] (1) In a nitrogen atmosphere at 30℃, 25.0 kg of isopropanol was pumped into a 2000 L reactor, followed by the dropwise addition of 120.0 kg of sodium hypochlorite aqueous solution (solute mass concentration 10%). The reaction was carried out at 10℃ for 1 h. Then, 50.0 kg of ammonia-methanol solution was added, the temperature was raised to 40℃, and the reaction was carried out for 1.5 h. The product content was controlled until it was greater than 98%. The excess methanol and ammonia were removed by distillation under reduced pressure (-0.85 MPa) at 40℃. 95.0 kg of acetonitrile was pumped in, followed by the addition of 14.0 kg of sodium hydroxide in batches, and the mixture was stirred until clear. The internal temperature of the reactor was lowered to 50℃, and 46.0 kg of benzyl chloride was added dropwise. The temperature inside the reactor was maintained at 50℃, and the mixture was stirred for 1 h until the reaction was completed. After the reaction was completed, 125.0 kg of water was pumped into the system, the system temperature was lowered to 20℃, and the mixture was stirred for 10 min. The organic phase was drawn back into the reactor, and 34.0 kg of saturated sodium chloride solution was drawn into the reactor. The mixture was stirred for 30 min and allowed to stand for 30 min. Then, vacuum distillation was performed at 30 °C and a vacuum degree of -0.085 to -0.095 MPa to concentrate the solution to an oily state.

[0052] (2) Maintaining the temperature at 30°C, the organic phase was drawn back into the reactor. Warm water at 60°C was introduced into the jacket. When the temperature inside the system rose to 50°C, 64.0 kg of hydrochloric acid was added. After the addition was complete, the mixture was kept warm and stirred for 30 min. After the system temperature dropped to 20°C, crystallization was carried out by stirring for 1 h. The mixture was then discharged into a centrifuge. The reactor was rinsed with 7.0 kg of methanol and centrifuged for another 0.5 h. The mixture was dried at 50°C with forced air for 12 h until the moisture content in the product was <0.5%, thus obtaining the final product OBH.

[0053] Comparative Example 1

[0054] A method for preparing an avibactam intermediate, differing from Example 1 in that it uses acetone oxime as the starting material, includes the following steps:

[0055] (1) Methanol (1L, 5V) and acetone oxime (200g, 1eq) were added to a three-necked reaction flask. After clarification, the temperature was controlled at 50℃. Sodium hydroxide (224g, 1.3eq) was added in portions. After the addition was complete, the mixture was stirred for 0.5h. The system was a transparent liquid with a small amount of solid precipitating out. Benzyl chloride (283.6g, 1.05eq) was added dropwise at 15℃. The system gradually turned into a white suspension. After the addition was complete, the mixture was kept at 50℃ for 1h. HPLC analysis was performed. Water (1L, 5V) was added and stirred until clarification. The mixture was extracted with petroleum ether (1L, 5V) until no product was found in the aqueous phase. The organic phases were combined and evaporated to dryness at 30℃ to obtain intermediate OBH01 (334.0g, yield 74.89%).

[0056] (2) Maintaining the temperature at 30°C, the organic phase was drawn back into the reactor, and warm water at 60°C was introduced into the jacket. When the temperature inside the system rose to 50°C, 300.0 g of hydrochloric acid was then drawn in. After the addition was complete, the mixture was kept warm and stirred for 30 min. After the system temperature dropped to 20°C, the mixture was stirred for 1 h, filtered, and washed with 50 g of methanol. The product was dried in a forced-air dryer at 50°C for 12 h until the moisture content in the product was <0.5%, thus obtaining the final product OBH.

[0057] The reaction process in step (1) above is as follows:

[0058]

[0059] Comparative Example 2

[0060] A method for preparing an avibactam intermediate, differing from Example 1 in that benzyl chloride is added dropwise at 70°C, specifically including the following steps:

[0061] (1) Using a one-pot method, under a nitrogen atmosphere, isopropanol (200 g, 1.0 eq) was added to a three-necked flask, followed by an aqueous solution of 400.0 g ammonia-methanol and 960.0 g sodium hypochlorite (solute mass concentration 10%). The temperature was raised to 50 °C, and an oxidative addition reaction was initiated for 2.5 h. Excess methanol and ammonia were removed by distillation. Without removing the solid, methanol (1 L, 5V) was added directly. The temperature was controlled at 45 °C, and sodium hydroxide (224 g, 1.3 eq) was added in portions. After the addition was complete, the mixture was stirred for 0.5 h. The system was a transparent liquid with a small amount of solid precipitating out. Benzyl chloride (283.6 g, 1.05 eq) was added dropwise at 70 °C, and the system gradually turned into a white suspension. After the addition was complete, the mixture was kept at 15 °C for 1 h, and the reaction was stopped by HPLC analysis. Add water (1L, 5V), stir to clarify, extract with petroleum ether (1L, 5V) until no product is found in the aqueous phase, combine the organic phases, and evaporate to dryness at 30°C to obtain intermediate OBH01 (317.4g, yield 71.09%).

[0062] (2) Maintaining the temperature at 30°C, the organic phase was drawn back into the reactor, and warm water at 60°C was introduced into the jacket. When the temperature inside the system rose to 50°C, 300.0 g of hydrochloric acid was then drawn in. After the addition was complete, the mixture was kept warm and stirred for 30 min. After the system temperature dropped to 20°C, the mixture was stirred for 1 h, filtered, and washed with 50 g of methanol. The product was dried in a forced-air dryer at 50°C for 12 h until the moisture content in the product was <0.5%, thus obtaining the final product OBH.

[0063] Comparative Example 3

[0064] The only difference between this comparative example and Example 1 is that in step (1), benzyl chloride is added dropwise at 35°C, the temperature of the substitution reaction is replaced with 35°C, and the reaction time is extended to 16h.

[0065] Product effectiveness test

[0066] 1. Product Specifications

[0067] The liquid phase spectrum of the OBH prepared in Example 1 is as follows: Figure 1 As shown in the figure, the OBH prepared in Example 1 has a purity of 99.92%, which is relatively high. Figure 1 In the table, Absorbance is the absorbance, Integration results are the integral results, total is the total, Area is the area, Retention Time is the retention time, Height is the height, Relative Area is the relative area, Resolution is the resolution, and plates is the number of plates.

[0068] 2. Yield and purity

[0069] The yield is calculated using the formula: Y = (M2 / 159.6) / (M1 / 126.6) × 100%.

[0070] Where M1: weight of acetone oxime; M2: weight of OBH; Y: molar yield.

[0071] Table 1 Yields of each embodiment and comparative example

[0072] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 yield 85％ 81.2％ 83.5％ 63.7％ 64.1％ 69.5％ purity 99.92％ 99.5％ 99.7％ 99.5％ 93.2％ 94.3％

[0073] As shown in the table above, the OBH yield of the products in Examples 1-3 of this invention can reach 81.2-85%, and the purity can reach 99.5-99.92%. Both the yield and purity are higher than those of Comparative Examples 1-3, indicating that the reaction has good stability and the single-step reaction time does not exceed 3 hours, resulting in a short preparation time.

[0074] Comparative Example 1 directly used acetone oxime as the starting material, which not only resulted in a long reaction time but also a low OBH yield.

[0075] In Comparative Example 2, the addition of benzyl chloride at a higher temperature and the subsequent substitution reaction triggered a side reaction, resulting in a decrease in both the yield and purity of OBH.

[0076] Comparative Example 3 lowered the temperature of the substitution reaction, which resulted in the raw materials not reacting completely. The reaction time needed to be extended to maximize the utilization of the raw materials. However, the reaction was carried out in an alkaline environment for a long time, which led to an increase in side reactions. As a result, the yield and purity of OBH decreased.

Claims

1. A method for preparing an avibactam intermediate, characterized in that, Includes the following steps: In a protective atmosphere, isopropanol and an oxidant are first mixed, then an ammonia source is added to carry out an oxidative addition reaction. A solvent, a basic substance, and benzyl halide are then added sequentially to carry out a substitution reaction. An acidic substance is then added to react with the avibactam intermediate. Benzyl halide is added at 40-60°C. The substitution reaction temperature is 40-60°C, and / or the substitution reaction time is 1-3 hours. The structure of the avibactam intermediate is shown in formula (Ⅰ):

2. The preparation method according to claim 1, characterized in that, The isopropanol and oxidant are mixed at 5-15°C, wherein the oxidant is added dropwise to the isopropanol for 0.5-1.5 hours. Then, an ammonia source is added, and the temperature is raised to 30-50°C for an oxidative addition reaction for 0.5-2 hours.

3. The preparation method according to claim 1, characterized in that, The mass ratio of isopropanol, benzyl halide, acidic substance, and basic substance is 1:(1-2.0):(2-3.0):(0.1-1.0).

4. The preparation method according to claim 1, characterized in that, Before adding the ammonia source, the ammonia source is first dissolved in methanol to obtain a mixed solution of ammonia and methanol, and then mixed with isopropanol and oxidant.

5. The preparation method according to claim 1, characterized in that, After the oxidative addition reaction, the solvent is removed.

6. The preparation method according to claim 5, characterized in that, After removing the solvent, there is no need to remove the solid; instead, the solvent, alkaline substance, and benzyl halide are directly added to carry out the substitution reaction.

7. The preparation method according to claim 1, characterized in that, The solvent is methanol and / or acetonitrile.

8. The preparation method according to claim 1, characterized in that, The alkaline substance is at least one of sodium hydroxide, potassium carbonate, and triethylamine.

9. The preparation method according to claim 1, characterized in that, The acidic substance is hydrochloric acid.

10. The preparation method according to claim 1, characterized in that, The protective atmosphere is at least one of nitrogen, helium, neon, and argon.

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