Preparation method of cephalosporin antibacterial key intermediate

Abstract

The invention discloses a preparation method of a cephalosporin antibacterial key intermediate, and belongs to the technical field of organic synthesis. The process comprises the following four steps of: 1, reacting tetrahydropyrrole and methyl acrylate in an organic solvent to generate 3-pyrrolidine methyl propionate; step 2, enabling the methyl 3-pyrrolidine propionate and propane diamine to react in an organic solvent to generate N-3-aminopropyl-3-(pyrrolidine-1-yl) propanamide; step 3, the N-3-aminopropyl-3-(pyrrolidine-1-yl) propanamide and the borane ammonia complex are subjected to a reaction in an organic solvent containing acid, and 1-(3-pyrrolidinepropyl)-1, 3-propane diamine is generated; and 4, carrying out a reaction on the 1-(3-pyrrolidinepropyl)-1, 3-propane diamine and 2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzoic acid in an organic solvent under the action of a condensing agent to generate 2-chloro-N-(3-(2-chloro-3, 4-bis ((4-methoxybenzyl) oxy) benzamide) propyl)-3, 4-bis ((4-methoxybenzyl) oxy)-N-(3-(pyrrolidine-1-yl) propyl) benzamide. According to the technical scheme, the steps are simple, the process is simple and reliable, industrial production is easy, and a new synthesis way is provided for the compound.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a key cephalosporin antibacterial intermediate. Background Art

[0002] The development of antimicrobial treatment options has become a continuous challenge facing today's society. Antimicrobial drugs include various antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones and other chemically synthesized drugs, among which β-lactam antibiotics are a very important class. So far, literature research has reported or a variety of β-lactamase drugs have been launched on the market, which has become an extremely important antimicrobial drug in clinical practice. However, the problem of drug resistance against β-lactam drugs is becoming more and more serious, and more and more bacteria have acquired resistance by producing β-lactamase and degrading β-lactamase drugs.

[0003] The emergence of Gram-negative bacteria that have become highly resistant to β-lactamase drugs (including cephalosporins and carbapenems) has caused great clinical application problems. Such resistance is caused by the production of A or D type serine β-lactamases and B type metallo-β-lactamases that extend their substrate spectrum. Metallo-β-lactamases are known to be one of the reasons for the acquisition of multi-drug resistance in Gram-negative bacteria. However, the need to develop cephalosporin compounds with more effective antibacterial activity, especially against Gram-negative bacteria that produce multiple β-lactamases, is a difficult problem in the current field of antibacterial drug research.

[0004] According to literature reports (Antimicrob Agents Chemother. 1982, 22 (2), 181–185), cephalosporin compounds containing catechol groups in their molecules have high anti-Gram-negative bacterial activity. 3+ Form an integration complex, so that the compound passes through the Fe 3+The transport system (tonB-dependent transport system) effectively binds to the bacteria. This Trojan horse strategy makes it more concentrated in the periplasmic space (the narrow space between the outer membrane and the cell wall) and binds to the receptor to inhibit the synthesis of the bacterial cell wall. Therefore, the compounds with catechol or similar structures at the 3-side chain or 7-side chain of the cephalosporin skeleton have been studied (EP0416410B1). Cefiderocol is a new type of iron carrier cephalosporin (WO2010050468; WO2017216765; Eur.JMed.Chem.2018,155,847-868). Currently, the FDA (U.S. Food and Drug Administration) has approved Fetroja (cefiderocol) of Shionogi Pharmaceutical for the treatment of complicated urinary tract infections (cUTI) in patients aged 18 years and above, including kidney infections caused by sensitive Gram-negative bacteria.

[0005] CN116528874 discloses the following compounds or pharmaceutically acceptable salts thereof, which can exhibit an effective antibacterial spectrum against various bacteria such as Gram-negative bacteria.

[0006]

[0007] When the existing route WO202215214 involves the step of coupling pyrrolidine, there are byproducts of deprotection groups, the yield is very low, and the product is complex and difficult to separate.

[0008] In summary, the synthesis steps of 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide in the prior art are complicated, the amount of three wastes is large, and the comprehensive cost is high. Therefore, it is particularly important to develop a synthetic route with a simple route, simple and reliable process, low cost and suitable for industrial production. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide, which has simple steps, simple and reliable processes, and is easy to industrialize. The preparation method has a simple synthesis route, readily available raw materials, no solid waste is generated, and the process is more environmentally friendly.

[0010] The synthetic route of the key cephalosporin antibacterial intermediate of the present invention is as follows:

[0011]

[0012] In the first step, tetrahydropyrrole and methyl acrylate undergo Michael addition reaction in an organic solvent to generate methyl 3-pyrrolidinepropionate.

[0013] Furthermore, in the above technical solution, the molar ratio of tetrahydropyrrole to methyl acrylate is 1:1-1.5.

[0014] Furthermore, in the above technical solution, the temperature is controlled at 0-5°C when tetrahydropyrrole is added.

[0015] In the second step, methyl 3-pyrrolidinepropionate and propylenediamine undergo amine ester exchange reaction in an organic solvent to generate N-3-aminopropyl-3-(pyrrolidin-1-yl)propionamide.

[0016] Furthermore, in the above technical solution, the organic solvent is selected from a mixture of one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0017] Furthermore, in the above technical solution, the molar ratio of methyl 3-pyrrolidinepropionate to propylenediamine is 1:1-1.5.

[0018] In the third step, N-3-aminopropyl-3-(pyrrolidin-1-yl) propionamide and borane amine complex undergo reduction reaction in an acid-containing organic solvent to generate 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine.

[0019] Furthermore, in the above technical solution, the acid is selected from trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, trifluoroacetic acid or trimethylsilyl trifluoromethanesulfonate.

[0020] Furthermore, in the above technical solution, the organic solvent is selected from a mixture of one or more of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, and toluene, and 1,4-dioxane is preferred.

[0021] This step of the reaction avoids the use of traditional lithium aluminum tetrahydride reagents, which are easy to ignite and form a viscous system if not properly post-processed, making it impossible to effectively post-process. After optimization, when using NH3-BH3 reagents, the reaction solvent and acid have a significant effect on the system, among which: when using trifluoromethanesulfonic acid, the reaction in methyl tert-butyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran has a yield of less than 20%, and dioxane has the best effect, with a yield of more than 80%; when using hydrochloric acid and sulfuric acid, there is almost no reaction, and the best combination system is a combination of trifluoromethanesulfonic acid or trifluoromethanesulfonic anhydride and dioxane.

[0022] In the fourth step, 1-(3-pyrrolidinopropyl)-1,3-propylenediamine and 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid undergo an acid-amine condensation reaction in an organic solvent under the action of a condensing agent to generate 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide.

[0023] Furthermore, in the above technical solution, the condensing agent is selected from HBTU, HATU, HDMA, HOBT and EDCI.

[0024] Furthermore, in the above technical solution, the organic solvent is selected from a mixture of one or more of toluene, heptane, dichloromethane, dichloroethane and dioxane.

[0025] Furthermore, in the above technical solution, the molar ratio of 1-(3-pyrrolidinopropyl)-1,3-propylenediamine and 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid is 1:2-3.

[0026] Compared with the prior art, the present invention has the following significant advantages:

[0027] A. The present invention avoids the disadvantages of long synthesis route and complicated reaction steps, and the cost is lower;

[0028] B. The present invention is more operable in actual production;

[0029] C. The comprehensive production cost of the present invention is greatly reduced compared with the currently known processes, and the synthesis process is more competitive in the market.

[0030] Beneficial effects of the present invention

[0031] The core points of the present invention are: using tetrahydropyrrole, methyl acrylate, propylenediamine and 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid as raw materials, shortening the synthesis route, avoiding the use of dangerous reagents, and reducing the cost of raw materials. The technical scheme of the present invention is simple and stable to operate, the products of each step are easy to separate, the yield is high, and it is environmentally friendly, providing a new synthesis route for the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The HPLC spectrum of 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide obtained in Example 1;

[0033] Figure 2This is the HNMR spectrum of 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide obtained in Example 1. DETAILED DESCRIPTION

[0034] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0035] Example 1

[0036] first step:

[0037] Tetrahydropyrrole (30 g, 421.82 mmol) was added to a solution of methyl acrylate (36.31 g, 421.82 mmol) in dichloromethane (150 mL) at 0-5°C under temperature control. The reaction solution was heated to room temperature and stirred for 4 hours. After the reaction, the solution was dried by spin drying to obtain methyl 3-pyrrolidinepropionate (64.98 g, yield 98%).

[0038] Step 2:

[0039] A methanol (300 mL) solution of methyl 3-pyrrolidinepropionate (60 g, 381.65 mmol) and propylenediamine (42.44 g, 572.48 mmol) was heated to about 80°C and stirred for 2 hours. After the reaction, N-3-aminopropyl-3-(pyrrolidin-1-yl)propionamide (61.61 g, yield 81%) was obtained by recrystallization with ethanol.

[0040] Step 3:

[0041] Under nitrogen protection, borane ammonia complex (46.46 g, 1.51 mol) was added to a 1,4-dioxane (300 mL) solution of N-3-aminopropyl-3-(pyrrolidin-1-yl) propionamide (60 g, 301.06 mmol) and trifluoromethanesulfonic acid (45.19 g, 301.1 mmol), heated to 80°C and stirred for 5 hours, then the reaction temperature was lowered to room temperature and the product was purified by silica gel column chromatography. After elution with petroleum ether as eluent, the solvent was decompressed and dried to obtain 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine (50.77 g, yield 91%).

[0042] Step 4:

[0043] EDCI (113.54 g, 592.26 mmol) and HOBT (80.03 g, 592.26 mmol) were added to a solution of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (254 g, 592.26 mmol) and 1-(3-pyrrolidinopropyl)-1,3-propylenediamine (50 g, 269.82 mmol) in dichloromethane (1200 mL), and the reaction solution was heated to room temperature. The mixture was stirred for 6 hours, and the solution was poured into ice water. After filtering, the product was purified by silica gel column chromatography. After elution with petroleum ether as eluent, the solvent was dried under reduced pressure to give 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide (230.95 g, yield 85%).

[0044] Example 2

[0045] first step:

[0046] Tetrahydropyrrole (1 g, 14.06 mmol) was added to a solution of methyl acrylate (1.45 g, 16.84 mmol) in dichloromethane (5 mL) at 0-5°C under temperature control. The reaction solution was heated to room temperature and stirred for 4 hours. After the reaction, the solution was dried by spin drying to obtain methyl 3-pyrrolidinepropionate (2.10 g, yield 95%).

[0047] Step 2:

[0048] A solution of methyl 3-pyrrolidinepropionate (2 g, 12.72 mmol) and propylenediamine (1.23 g, 16.54 mmol) in N,N-dimethylformamide (10 mL) was heated to about 100°C and stirred for 2 hours. After the reaction, N-3-aminopropyl-3-(pyrrolidin-1-yl)propionamide (2.11 g, yield 83%) was obtained by recrystallization with ethanol.

[0049] Step 3:

[0050] Under nitrogen protection, borane ammonia complex (1.55 g, 50.18 mmol) was added to a 1,4-dioxane (10 mL) solution of N-3-aminopropyl-3-(pyrrolidin-1-yl) propionamide (2 g, 10.04 mmol) and trifluoromethanesulfonic anhydride (4.29 g, 15.2 mmol), heated to 80 ° C and stirred for 4 hours, then the reaction temperature was lowered to room temperature and the product was purified by silica gel column chromatography. After elution with petroleum ether as the eluent, the solvent was decompressed and dried to obtain 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine (1.71 g, yield 92%).

[0051] Step 4:

[0052] HATU (9.07 g, 23.85 mmol) was added to a toluene (50 mL) solution of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (10.23 g, 23.85 mmol) and 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine (1.7 g, 9.17 mmol), and the reaction solution was stirred at room temperature for 6 hours. The solution was poured into ice water, filtered, and the product was purified by silica gel column chromatography. After elution with petroleum ether as an eluent, the solvent was dried under reduced pressure to obtain 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide (7.95 g, yield 86%).

[0053] Example 3

[0054] first step:

[0055] Tetrahydropyrrole (20 mg, 0.28 mmol) was added to a solution of methyl acrylate (31.5 mg, 0.36 mmol) in dichloromethane (1 mL) at 0-5°C under temperature control. The reaction solution was heated to room temperature and stirred for 4 hours. After the reaction, the solution was dried by spin drying to obtain methyl 3-pyrrolidinepropionate (42.4 mg, yield 96%).

[0056] Step 2:

[0057] A solution of methyl 3-pyrrolidinepropionate (42 mg, 0.27 mmol) and propylenediamine (21.8 mg, 0.29 mmol) in ethanol (1 mL) was heated to about 80°C and stirred for 2 hours. After the reaction, N-3-aminopropyl-3-(pyrrolidin-1-yl)propionamide (44.7 mg, yield 84%) was obtained by recrystallization with ethanol.

[0058] Step 3:

[0059] Under nitrogen protection, borane amine complex (27 mg, 0.88 mmol) was added to a 1,4-dioxane (2 mL) solution of N-3-aminopropyl-3-(pyrrolidin-1-yl) propionamide (44 mg, 0.22 mmol) and trifluoromethanesulfonic acid (33 mg, 0.22 mmol), heated to 80 ° C and stirred for 4 hours, then the reaction temperature was lowered to room temperature and the product was purified by silica gel column chromatography. After elution with petroleum ether as the eluent, the solvent was decompressed and dried to obtain 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine (36.8 mg, yield 90%).

[0060] Step 4:

[0061] HBTU (178.25 mg, 0.47 mmol) was added to a solution of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (199.96 mg, 0.47 mmol) and 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine (36 mg, 0.19 mmol) in dioxane (2 mL), and the reaction solution was stirred at room temperature for 6 hours. The solution was poured into ice water, filtered, and the product was purified by silica gel column chromatography. After elution with petroleum ether as an eluent, the solvent was dried under reduced pressure to obtain 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide (164.33 mg, yield 84%).

[0062] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of cephalosporin antibiotics, characterized in that: The steps include: In the first step, tetrahydropyrrole and methyl acrylate react in an organic solvent to generate methyl 3-pyrrolidine propionate; In the second step, methyl 3-pyrrolidinepropionate and propylenediamine react in an organic solvent to generate N-3-aminopropyl-3-(pyrrolidin-1-yl)propionamide; In the third step, N-3-aminopropyl-3-(pyrrolidin-1-yl) propionamide and borane amine complex react in an acid-containing organic solvent to generate 1-(3-pyrrolidinylpropyl)-1,3-propylenediamine; In the fourth step, 1-(3-pyrrolidinopropyl)-1,3-propylenediamine and 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid react in an organic solvent under the action of a condensing agent to generate 2-chloro-N-(3-(2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzamide)propyl)-3,4-bis((4-methoxybenzyl)oxy)-N-(3-(pyrrolidin-1-yl)propyl)benzamide.

2. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the first step, the molar ratio of tetrahydropyrrole to methyl acrylate is 1:1-1.

5.

3. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the first step, the temperature is controlled at 0-5°C when tetrahydropyrrole is added.

4. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the second step, the organic solvent is selected from a mixture of one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, and N,N-dimethylformamide.

5. The method for preparing the key intermediate of the cephalosporin antibacterial compound according to claim 1, characterized in that: In the second step, the molar ratio of methyl 3-pyrrolidinepropionate to propylenediamine is 1:1-1.

5.

6. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the third step, the acid is selected from trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, trifluoroacetic acid or trimethylsilyl trifluoromethanesulfonate.

7. The method for preparing a cephalosporin antibacterial key intermediate according to claim 1, characterized in that: In the third step, the organic solvent is selected from a mixture of one or more of dichloromethane, 1,2-dichloroethane, 1,4-dioxane and toluene.

8. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the fourth step, the condensing agent is selected from HBTU, HATU and HDMA.

9. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the fourth step, the organic solvent is selected from a mixture of one or more of toluene, heptane, dichloromethane, dichloroethane and dioxane.

10. The method for preparing the key cephalosporin antibacterial intermediate according to claim 1, characterized in that: In the fourth step, the molar ratio of 1-(3-pyrrolidinopropyl)-1,3-propylenediamine to 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid is 1:2-3.

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