A process for the preparation of a vaborbactam intermediate

Abstract

The application belongs to the technical field of compounds and provides a preparation method of a febuxostat intermediate. In a protective atmosphere, the method comprises the following steps: mixing a tert-butyl acetate solution, an alkaline substance and acrolein, performing an addition reaction at 0-5 DEG C for 0.1-3 h, and then adding a biological enzyme catalyst to react at 5-10 DEG C for 1-3 h to obtain the febuxostat intermediate. The application adopts a gradient temperature control mode, adds the alkaline substance in a lower temperature environment at 0-5 DEG C and performs an addition reaction to ensure high purity and high yield of the product, then adds the biological enzyme catalyst and increases the temperature to separate the racemic substance, so as to ensure a faster reaction rate and shorten the reaction time. The addition reaction can be completed within 3 h, the whole preparation process takes no more than 6 h, the yield, purity and chiral purity are high, the yield can reach 42-45%, the purity can reach 99.0%-99.5%, and the chiral purity can reach more than 99%.

Description

Technical Field

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

[0002] Faborbactam, chemically named (3R,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxorane-6-acetic acid, is a broad-spectrum cyclic borate pharmacophore β-lactamase inhibitor. It exhibits particularly strong activity against KPC (carbapenemase), CTX-M (CTX-M type β-lactamase), SHV (SHV type β-lactamase), and CMY (C class carbapenemase), and has wide applications in the pharmaceutical field. The structure of faborbactam is shown in formula (II) below:

[0003]

[0004] The preparation of faborbactam involves the synthesis of the faborbactam intermediate FPB02 (chemical name: tert-butyl 3-hydroxy-4-pentenoate, CAS: 1040390-31-5), the structure of which is shown in formula (Ⅰ) below:

[0005]

[0006] Traditional methods for preparing FPB02 intermediates generally suffer from long reaction times (at least 16 hours are required to synthesize FPB02 alone, and subsequent steps may involve the resolution of racemic substances) and low yields (generally 10-20%). Chinese patent (publication number CN105399770A) reports a synthetic process for methyl 3-hydroxy-4-pentenoate and its analogues. This route uses epichlorohydrin as a starting material, adds sodium acetylenide, and synthesizes the intermediate (2R)-1-chloro-2-hydroxy-4-pentyne under the catalysis of Salen Co (a condensate-Co complex of (R,R)-1,2-diphenylethylenediamine and 2-hydroxy-5-methyl-3-tert-butylbenzaldehyde). A cyano group is then grafted onto the intermediate by adding an aqueous sodium cyanide solution. Finally, methanol and hydrochloric acid are added to yield methyl (3R)-hydroxy-5-octylenate, with a molar yield exceeding 100%. However, the catalyst Salen Co is very expensive, and highly toxic sodium cyanide is used, thus limiting the applicability of this route for practical commercial applications. The above synthetic route is shown below:

[0007]

[0008] Therefore, there is an urgent need to develop a method for preparing Fabobacterium intermediate (FPB02 intermediate) with high yield, avoiding the use of highly toxic and expensive catalysts, maximizing the utilization of raw materials, and shortening the reaction time. Summary of the Invention

[0009] 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 a faborazan intermediate. The method for preparing the FPB02 intermediate of this invention first involves an addition reaction of tert-butyl acetate, acrolein, and a basic substance to obtain a racemic form containing FPB02 (FPB01), followed by resolution by a bio-enzymatic catalyst to obtain FPB02. The method achieves high yield (41-45%), high product purity (99.2%-99.5%), high chiral purity (99.2-99.5%), short reaction time (the addition reaction to obtain FPB02 does not exceed 3 hours, and the entire preparation process takes no more than 6 hours), good reaction stability, no need for highly toxic and expensive catalysts, low production cost, suitability for industrial production, easy product separation and purification, simple and safe operation, minimal production waste, and simple treatment, making it green and efficient.

[0010] The first aspect of the present invention provides a method for preparing a faborabactam intermediate.

[0011] Specifically, a method for preparing a faborazan intermediate (FPB02) includes the following steps:

[0012] In a protective atmosphere, a solution of tert-butyl acetate, an alkaline substance, and acrolein are mixed and subjected to an addition reaction. A bio-enzyme catalyst is then added to carry out the reaction, thereby obtaining the faborabactam intermediate.

[0013] The addition reaction is carried out at a temperature of 0-5°C and / or for a duration of 0.1-3 hours.

[0014] The reaction temperature with added bio-enzyme catalyst is 5-10℃, and / or the reaction time with added bio-enzyme catalyst is 1-3h;

[0015] The faborabactam intermediate has the molecular structure shown in formula (Ⅰ);

[0016]

[0017] This invention utilizes tert-butyl acetate (CAS: 540-88-5), acrolein, and an alkaline substance in an addition reaction, followed by the addition of a bio-enzyme catalyst to resolve the racemic substances and obtain FPB02. Because this invention employs a gradient temperature control method, the alkaline substance is first added in a low-temperature environment of 0-5℃ to avoid ester hydrolysis under alkaline conditions caused by excessively high temperatures, thus ensuring high purity and high yield of the product. Furthermore, the addition reaction is short (completed within 3 hours). However, since optical isomers are present, a bio-enzyme catalyst is added and the temperature is increased to resolve the racemic substances, ultimately obtaining FPB02. The addition of the enzyme and the increase in temperature ensure a relatively fast reaction rate and shortened reaction time, resulting in a short overall preparation process.

[0018] Preferably, the temperature of the addition reaction is 0-3°C, and / or the time of the addition reaction is 0.5-2.5 h.

[0019] Preferably, the temperature at which the bio-enzyme catalyst is added for the reaction is 6-9°C, and / or the reaction time is 1.5-2.5 h.

[0020] Preferably, the alkaline substance is at least one of lithium diisopropylamino (LDA), lithium aluminum hydride, and N,N-diisopropylethylamine.

[0021] Preferably, the alkaline substance is added dropwise to reduce the formation of byproducts.

[0022] Preferably, the bio-enzyme catalyst is a lipase. Using lipase as a bio-enzyme catalyst not only provides excellent separation efficiency but also adsorbs and rapidly separates reaction byproducts, thus advancing the reaction. Furthermore, it requires small amounts, is widely available, inexpensive, produces high-purity products, and is highly safe.

[0023] Preferably, the bio-enzyme catalyst is a lipase solution with a solute mass concentration of 0.5-3%.

[0024] More preferably, the bio-enzyme catalyst is a lipase solution with a solute mass concentration of 1-2%.

[0025] Preferably, the mass ratio of tert-butyl acetate, acrolein, alkaline substance and bio-enzyme catalyst is 1:(0.1-0.5):(1-1.5):(0.4-0.8).

[0026] More preferably, the mass ratio of tert-butyl acetate, acrolein, alkaline substance and bio-enzyme catalyst is 1:(0.3-0.5):(1-1.3):(0.4-0.6).

[0027] Preferably, the method for preparing the tert-butyl acetate solution includes dissolving tert-butyl acetate in a solvent to obtain the tert-butyl acetate solution.

[0028] Preferably, the solvent in the tert-butyl acetate solution is dichloromethane and / or ethyl acetate.

[0029] More preferably, the solvent in the tert-butyl acetate solution is ethyl acetate.

[0030] Preferably, the protective atmosphere is at least one of nitrogen, helium, neon, argon, krypton, and xenon.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] This invention involves mixing a tert-butyl acetate solution, an alkaline substance, and acrolein in a protective atmosphere for an addition reaction, followed by the addition of a bio-enzyme catalyst to prepare a faborazan intermediate. Specific conditions for the addition reaction and the bio-enzyme catalyst reaction are also defined. This invention employs a gradient temperature control method, first adding the alkaline substance and conducting the addition reaction at a lower temperature of 0-5°C to ensure high purity and high yield of the product. Then, a bio-enzyme catalyst is added and the temperature is increased to resolve the racemic substance, ensuring a faster reaction rate and shortening the reaction time. The addition reaction can be completed within 3 hours, and the entire preparation process takes no more than 6 hours, achieving a high yield (41-45%), high product purity (99.2%-99.5%), and high chiral purity (99.2-99.5%). Attached Figure Description

[0033] Figure 1 The image shows the chiral liquid chromatogram of FPB02, the faborabactam intermediate obtained in Example 1 of this invention. Detailed Implementation

[0034] 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.

[0035] 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.

[0036] The raw materials used in the various embodiments and comparative examples of this invention are as follows:

[0037] Bio-enzyme catalyst: 1% lipase solution, derived from porcine pancreas, model 9001-62-1, activity ≥30000μ / g, off-white or pale yellow powder, purchased from Shanghai Yiji Industrial Co., Ltd.

[0038] Example 1

[0039] A method for preparing a faborazine intermediate (FPB02) includes the following steps:

[0040] (1) At 30°C, under nitrogen protection, ethyl acetate was added to a 100L reactor, followed by 10.0kg of tert-butyl acetate and 5.0kg of acrolein. The mixture was stirred to dissolve, cooled to 5°C, and stirred for 10 minutes. The mixture was kept at 5°C and 13.0kg of tetrahydrofuran solution of LDA (diisopropylaminolithium) was added dropwise. The dropwise addition process took 30 minutes. After the dropwise addition was completed, the mixture was kept at 5°C for 1 hour to carry out the addition reaction to obtain FPB01. Then, the temperature was controlled at 25°C and 24.0kg of water was added dropwise to the reactor to quench the reaction.

[0041] (2) Prepare 164.0 kg of 0.5 mol / L hydrochloric acid solution (i.e., 11.00 kg of concentrated hydrochloric acid dissolved in 153.0 kg of drinking water), then use the hydrochloric acid solution to adjust the pH of the reaction solution in step (1) to 4, then add vinyl ether and n-pentane in sequence, stir for 3 min, add 5 kg of lipase (1% solute mass fraction solution), and control the temperature at 5℃ for 2 h; monitor the reaction by liquid chromatography, after the conversion rate reaches 50%, keep warm at 5℃ and filter to remove lipase, wash the filter cake with ethyl acetate, separate the filtrate, add drinking water to the upper layer (product) and stir for 30 min, separate the layers, and distill the upper layer (product) under reduced pressure at 50℃ to remove ethyl acetate, and obtain FPB02 product after no fraction is distilled.

[0042] The addition reaction equation for step (1) above is as follows:

[0043]

[0044] Example 2

[0045] A method for preparing a faborabactam intermediate (FPB02) (replacing lithium diisopropylamino in step (1) of Example 1 with lithium aluminum hydride) specifically includes the following steps:

[0046] (1) At 30℃, under nitrogen protection, ethyl acetate was added to a 100L reactor, followed by 10.0kg of tert-butyl acetate and 5.0kg of acrolein. The mixture was stirred until dissolved, then cooled to 5℃ and stirred for 10min. 13.0kg of tetrahydrofuran solution of lithium aluminum hydride was added dropwise at 5℃ over 30min. After the addition was complete, the reaction was kept at 25℃ for 1h. 24.0kg of water was added dropwise to the reactor to quench the reaction.

[0047] (2) Prepare 164.0 kg of 0.5 mol / L hydrochloric acid solution (i.e., 11.00 kg of concentrated hydrochloric acid dissolved in 153.0 kg of drinking water). Then adjust the pH of the reaction solution to 4 with hydrochloric acid solution. Add vinyl ether and n-pentane in sequence, stir for 3 min, add 5 kg of lipase, and react at 5℃ for 2 h. Monitor the reaction by liquid chromatography. When the conversion rate reaches 50%, filter out the lipase at 5℃. Wash the filter cake with ethyl acetate. The filtrate separates into layers. Add drinking water to the upper layer (product) and stir for 20 min. Separate into layers. Distill the upper layer (product) under reduced pressure at 50℃ to remove ethyl acetate. Obtain FPB02 product after distillation until no fraction is distilled.

[0048] Example 3

[0049] A method for preparing a faborazine intermediate (FPB02) (replacing ethyl acetate in step (1) of Example 1 with dichloromethane) specifically includes the following steps:

[0050] (1) At 30℃, under nitrogen protection, dichloromethane was added to a 100L reactor, followed by 10.0kg of tert-butyl acetate and 5.0kg of acrolein. The mixture was stirred until dissolved, then cooled to 5℃ and stirred for 10min. 13.0kg of diisopropylaminolithium tetrahydrofuran solution was added dropwise at 5℃ over 30min. After the addition was complete, the reaction was kept at 25℃ for 1h. 24.0kg of water was added dropwise to the reactor to quench the reaction.

[0051] (2) Prepare 164.0 kg of 0.5 mol / L hydrochloric acid solution (i.e., 11.00 kg of concentrated hydrochloric acid dissolved in 153.0 kg of drinking water). Then adjust the pH of the reaction solution to 4 with hydrochloric acid solution. Add vinyl ether and n-pentane in sequence, stir for 3 min, add 5 kg of lipase, and react at 5℃ for 2 h. Monitor the reaction with liquid chromatography. After the conversion rate reaches 50%, filter out the lipase at 5℃. Wash the filter cake with dichloromethane. The filtrate separates into layers. Add drinking water to the upper layer (product) and stir for 30 min. Separate into layers. Distill the upper layer (product) under reduced pressure at 50℃ to remove dichloromethane. Obtain FPB02 product after distillation until no fraction is distilled.

[0052] Comparative Example 1

[0053] A method for preparing a faborazine intermediate (FPB02) includes the following steps:

[0054] (1) At 30℃, under nitrogen protection, ethyl acetate was added to a 250mL three-necked flask, followed by 20g of tert-butyl acetate and 10.0g of acrolein. The mixture was stirred until dissolved, cooled to 5℃, and stirred for 10min. 22.0g of diisopropylaminolithium tetrahydrofuran solution was added dropwise at 5℃ over 30min. After the addition was complete, the reaction was kept at 25℃ for 1h. Water was added dropwise to the three-necked flask to quench the reaction.

[0055] (2) Adjust the pH of the reaction solution to 4 with hydrochloric acid solution, then add vinyl ether and n-pentane in sequence, stir for 2 min, add 3.5 g of 2,2"-bis(diphenylphosphine)-1,1"-binaphthyl catalyst (BINAP, CAS No.: 76189-55-4), and react at 5℃ for 23 h. Monitor the reaction by liquid chromatography. The conversion rate reached 43%. Control the temperature at 5℃ and filter to remove the catalyst. Wash the filter cake with ethyl acetate. The filtrate separates into layers. Add drinking water to the upper layer (product) and stir for 30 min. Separate into layers. Distill the upper layer (product) under reduced pressure at 40℃ to remove ethyl acetate. After no fraction is obtained, 11.5 g of pale yellow oily product is obtained, with a yield of 38.89%.

[0056] The reaction route described above is as follows:

[0057]

[0058] Comparative Example 2 (Increasing the addition reaction temperature)

[0059] A method for preparing a faborazine intermediate (FPB02) differs from Example 1 in that step (1) involves the dropwise addition of lithium diisopropylamino at 15°C, specifically including the following steps:

[0060] (1) At 30℃, under nitrogen protection, ethyl acetate was added to a 250mL three-necked flask, followed by 20g of tert-butyl acetate and 10.0g of acrolein. The mixture was stirred until dissolved, cooled to 15℃, and stirred for 10min. 26.0g of diisopropylaminolithium tetrahydrofuran solution was added dropwise at 15℃ over 30min. After the addition was complete, the reaction was kept at 25℃ for 1h. 48g of water was added dropwise to the three-necked flask to quench the reaction.

[0061] (2) Adjust the pH of the reaction solution to 4 with hydrochloric acid solution, then add vinyl ether and n-pentane in sequence, stir for 2 min, add 10 g of lipase (1% solution), and react at 5℃ for 2 h. Monitor the reaction by liquid chromatography. When the conversion rate reaches 50%, filter out the lipase at 5℃. Wash the filter cake with ethyl acetate. The filtrate separates into layers. Add drinking water to the upper layer (product) and stir for 30 min. Separate into layers. Distill the upper layer (product) under reduced pressure at 50℃ to remove ethyl acetate. After no fraction is obtained, 9.2 g of pale yellow oily product is obtained, with a yield of 31.1%.

[0062] Comparative Example 3

[0063] A method for preparing a faborazine intermediate (FPB02) differs from Example 1 in that step (1) involves directly adding the LDA solution in one step (instead of adding it dropwise), specifically including the following steps:

[0064] (1) At 30℃, ethyl acetate was added to a 250mL three-necked flask, followed by 20g of tert-butyl acetate and 10.0g of acrolein. The mixture was stirred until dissolved, cooled to 15℃ and stirred for 10min. Then, 26.0g of LDA in tetrahydrofuran solution was added directly and the reaction was kept at 1h. The mixture was then quenched by adding 48g of water dropwise to the three-necked flask at 25℃.

[0065] (2) Adjust the pH of the reaction solution to 4 with hydrochloric acid solution, then add vinyl ether and n-pentane in sequence, stir for 2 min, add 10 g of lipase (1% solution), and react at 5℃ for 2 h. Monitor the reaction by liquid chromatography. After the conversion rate reaches 50%, filter out the lipase at 5℃. Wash the filter cake with ethyl acetate. The filtrate separates into layers. Add drinking water to the upper layer (product) and stir for 30 min. Separate into layers. Distill the upper layer (product) under reduced pressure at 50℃ to remove ethyl acetate. After no fraction is obtained, the product FPB02 is obtained, which is 5.92 g of brownish-yellow oil with a yield of 20.5%.

[0066] Product effectiveness test

[0067] 1. Structural characterization

[0068] The chiral pattern of FPB02 obtained in Example 1 is as follows: Figure 1 As shown in the figure, it can be determined from the figure that the final product structure of Example 1 is as shown in formula (Ⅰ), and the separation effect is excellent.

[0069] 2. Yield, purity, and chiral purity

[0070] The yield is calculated using the formula: Y = (M2 / 172.22) / (M1 / 116.16) × 100%;

[0071] Where M1: weight of tert-butyl acetate; M2: weight of FPB02; Y: molar yield.

[0072] Table 1. Yields, purity, and chirality of each example and comparative example.

[0073] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 yield 45％ 43％ 41％ 38.89％ 31.1％ 20.5％ purity 99.3％ 99.5％ 99.2％ 99.5％ 92.2％ 75.2％ Chiral purity 99.5％ 99.2％ 99.4％ 96.5％ 92.0％ 88.5％

[0074] As shown in the table above, the yield of Examples 1-3 of the present invention can reach 41-45%, the purity can reach 99.2-99.5%, and the chiral purity can reach 99.2-99.5%. The product yield, purity, and chiral purity of the present invention are all higher than those of Comparative Examples 1-3, indicating that the reaction has good stability. In addition, the reaction time is shortened (addition reaction does not exceed 3 hours).

[0075] Compared with Example 1, Comparative Example 1 replaced the lipase with a conventional chiral catalyst (BINAP). The purity difference was not significant, but the reaction cycle was significantly longer, requiring at least 23 hours. As a result, the final chiral purity did not reach the expected level, only 96.5%. Therefore, the catalytic efficiency of the bio-enzyme catalyst (lipase) is higher than that of the conventional catalyst, and the lipase selectivity is better.

[0076] Compared with Example 1, Comparative Example 2 increased the temperature of adding diisopropylaminolithium to 15°C. The addition reaction temperature was too high, which triggered side reactions, resulting in a decrease in the final yield, purity and chiral purity.

[0077] Compared with Example 1, Comparative Example 3 directly added the LDA solution to the reaction system all at once, resulting in an excessively high concentration of LDA in the system. This caused a competitive reaction, and LDA reacted with the previously generated FPB02 to produce byproducts. Therefore, the final yield, purity, and chiral purity all decreased.

Claims

1. A method for preparing a faborazine intermediate, comprising the following steps: In a protective atmosphere, a solution of tert-butyl acetate, an alkaline substance, and acrolein are mixed and subjected to an addition reaction. A bio-enzyme catalyst is then added to carry out the reaction, thereby obtaining the faborabactam intermediate. The addition reaction is carried out at a temperature of 0-5°C and / or for a duration of 0.1-3 hours. The reaction temperature with added bio-enzyme catalyst is 5-10℃, and / or the reaction time with added bio-enzyme catalyst is 1-3h; The faborabactam intermediate has the molecular structure shown in formula (Ⅰ); 2. The preparation method according to claim 1, characterized in that, The alkaline substance is at least one of lithium diisopropylamino, lithium tetrahydrocarbon, and N,N-diisopropylethylamine.

3. The preparation method according to claim 1, characterized in that, The alkaline substance is mixed by adding it dropwise.

4. The preparation method according to claim 1, characterized in that, The bio-enzyme catalyst is a lipase.

5. The preparation method according to claim 4, characterized in that, The bio-enzyme catalyst is a lipase solution with a solute mass concentration of 0.5-3%.

6. The preparation method according to claim 5, characterized in that, The bio-enzyme catalyst is a lipase solution with a solute mass concentration of 1-2%.

7. The preparation method according to claim 1, characterized in that, The mass ratio of tert-butyl acetate, acrolein, alkaline substance and bio-enzyme catalyst is 1:(0.1-0.5):(1-1.5):(0.4-0.8).

8. The preparation method according to claim 7, characterized in that, The mass ratio of tert-butyl acetate, acrolein, alkaline substance and bio-enzyme catalyst is 1:(0.3-0.5):(1-1.3):(0.4-0.6).

9. The preparation method according to claim 1, characterized in that, The solvent in the tert-butyl acetate solution is dichloromethane and / or ethyl acetate.

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

Images