Key intermediate of avibactam sodium and preparation method thereof

Abstract

The invention discloses a key intermediate of avibactam sodium and a preparation method thereof, comprising: dissolving a compound of formula 8 in a non-protonic polar organic solvent, and reacting with a carboxyl activator and an ammonia source in a one-pot manner in the presence of an organic base to obtain a key intermediate of avibactam sodium as shown in formula 2; the reaction mechanism is: the compound of formula 8 reacts with a carboxyl activator to obtain a compound of formula 9; the compound of formula 9 reacts with an ammonia source to generate a compound of formula 2; wherein LG in the compound of formula 9 is tert-butyloxycarbonyloxy, n-butyloxycarbonyloxy, isobutyloxycarbonyloxy, n-propyloxycarbonyloxy, isopropyloxycarbonyloxy, ethoxycarbonyloxy, methoxycarbonyloxy or benzyloxycarbonyloxy. The preparation method of the invention is simple to operate, has few by-products, and has high product yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a key intermediate of avibactam sodium and a preparation method thereof. Background Art

[0002] Ceftazidime-avibactam (CAZ-AVI) is a compound of the third-generation cephalosporin antibiotics ceftazidime and avibactam sodium (NXL104, AVE1330, compound of formula 1). Avibactam sodium contains a non-β-lactam structure and is a β-lactamase inhibitor. Avibactam sodium protects ceftazidime from degradation by β-lactamases and maintains the antibacterial activity of ceftazidime against isolated Enterobacteriaceae and Pseudomonas aeruginosa, which express multiple serine β-lactamases. Avibactam sodium alone has no direct antibacterial activity and does not affect the activity of ceftazidime against ceftazidime-sensitive bacteria or most anaerobic Gram-negative bacteria.

[0003] Ceftazidime was first marketed in 1985 under the trade name Approved for clinical use in the treatment of lower respiratory tract infections, skin and skin structure infections, urinary tract infections, bacterial sepsis, bone and joint infections, gynecological infections, intra-abdominal infections, and central nervous system infections. Ceftazidime has been shown to be used to treat complicated urinary tract infections caused by the following sensitive bacterial infections, including Pseudomonas aeruginosa, Enterobacter, Proteus, Klebsiella, and Escherichia coli, as well as severe intra-abdominal infections, including peritonitis caused by Escherichia coli, Klebsiella, Staphylococcus aureus (methicillin-sensitive strains), and polymicrobial infections caused by aerobic and anaerobic organisms.

[0004] The increasing prevalence of resistance to cephalosporins, especially in nosocomial infections, and the inherent high stability of carbapenems to numerous β-lactamases and AmpC β-lactamases have led to the increasing use of carbapenems. Although other β-lactams have been approved for combination use with β-lactamase inhibitor drugs, these drugs are not active against Ambler class A Klebsiella pneumoniae carbapenemases (KPCs), class B enzymes (metallo-β-lactamases), class C enzymes (such as AmpC), and may induce ESBL production. Avibactam sodium can inhibit class A ESBLs, KPCs, AmpC, and some class D enzymes. The clinical development program for CAZ-AVI is designed to address this unmet need.

[0005]

[0006] (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (compound of formula 2) is a key intermediate for the synthesis of avibactam sodium (compound of formula 1). There are many publicly reported synthesis methods, which are mainly divided into two categories, as shown below:

[0007]

[0008] Both synthetic routes start from (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylic acid alkyl ester oxalate 3 as the starting material, in particular, (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylic acid benzyl ester oxalate 3a (R=Bn) and (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate 3b (R=Et) or methyl ester oxalate 3c (R=Me) as the starting materials.

[0009] Route 1: (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylic acid alkyl ester 3 is treated with an ammonia source in the presence of an organic base in a suitable solvent, or its oxalate 3 is first treated with an appropriate base and then reacted with an ammonia source to obtain (2S,5R)-5-benzyloxyaminopiperidine-2-carboxamide (compound of formula 4). The 1-amino group of the compound of formula 4 is first protected with an appropriate protecting agent to obtain intermediate 5, and then a carbonyl cyclization reagent is first connected to the nitrogen of the benzyloxyamino group, and then a ring-closure reaction is carried out under the action of an activator to obtain the compound of formula 2.

[0010] Route 2, (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylic acid alkyl ester reacts with a carbonyl cyclizing agent in a suitable solvent, or its oxalate 3 is first treated with a suitable base in a suitable solvent, and then reacted with a carbonyl cyclizing agent to obtain (2S,5R)-6-benzyloxy-7-oxy-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid alkyl ester (Formula 7 compound). The Formula 7 compound is then hydrolyzed in a suitable alkali aqueous solution and organic solvent, and after acidification, (2S,5R)-6-benzyloxy-7-oxy-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (Formula 8 compound) is obtained. The Formula 8 compound is reacted with a suitable activator in the presence of an acid binding agent, and then reacted with a suitable ammonia source to obtain the Formula 2 compound.

[0011] A Chinese patent document with publication number CN 105294690 A (Aliscon 2016) discloses a method for synthesizing a compound of formula 2, and is applied to industrial mass production (Org. Process Res. Dev. 2016, 20, 1799-1805). The method utilizes the oxalate of (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid benzyl ester (compound of formula 3a) which is convenient to source, treats it with an aqueous solution of an inorganic base, and then performs amidation with a methanol solution of ammonia in toluene, thereby obtaining a compound (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxamide (compound of formula 4) with high yield. The carboxamide is in chlorobenzene, diisopropylethylamine (DIPEA) is used as an acid scavenger, and the 1-amino group is protected with fluorenyloxycarbonyl chloride. Then, carbonyldiimidazole (CDI) is used to first connect the imidazole carbonyl group on the nitrogen of the benzyloxyamino group, and finally, it is activated with diethylamine for deprotection cyclization reaction to obtain a compound of formula 2, and the total yield is 83%. The method has a high yield, and the synthesis of compound of formula 2 from compound of formula 4 through carbonyl cyclization can be completed in a "one-pot" reaction, and the operation is simple, and it has become a key intermediate for the scale-up production of raw materials (API). However, its disadvantage is that the carbonyl cyclization process, i.e. the addition of a carbonyl group, requires the use of expensive fluorenyloxycarbonyl chloride as a protecting agent, diisopropylethylamine as an acid binding agent, carbonyldiimidazole (CDI) as a carbonylating agent, and diethylamine as a cyclization reaction activator, which has poor atom economy and high production cost (Org. Process Res. Dev. 2016, 20, 1799-1805).

[0012]

[0013] Another synthetic route disclosed in the patent is to first dissolve the oxalate salt 3a of (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid benzyl ester in 2-methyltetrahydrofuran (2-MeTHF), treat it with an aqueous solution of potassium bicarbonate, and then react the organic phase with triphosgene in the presence of triethylamine to obtain (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester 7a, and then hydrolyze it with an aqueous solution of lithium hydroxide in acetone, acidify the obtained compound of formula 8, and then activate the carboxyl group with pivaloyl chloride in the presence of triethylamine in dichloromethane, and amidate it with concentrated ammonia water at -20 degrees to obtain (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 2. However, the yield of the four steps is only 36.8%. When the production is scaled up, the yield is less than 30% (Org. Process Res. Dev. 2016, 20, 1799-1805). Therefore, it is not suitable for large-scale industrial production.

[0014]

[0015] The patent also discloses a method for synthesizing (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 2 by directly amidating (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 2 with ammonium carbamate as ammonia source and under the action of immobilized Antarctic Candida lipase B (Novozyme 435), with a yield of 65%. Although this method has a good yield, the enzyme used is expensive, the amount used is large, the production cycle is long, and it is not suitable for industrial production.

[0016]

[0017] The Chinese patent document (2017) with publication number CN07417686 A discloses a method for directly synthesizing the compound of formula 2 using (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxamide 4 as a raw material, reacting with dimethyldichlorosilane in acetonitrile in the presence of diisopropylethylamine, first protecting the amino group at the 1-position, and then using carbonyldiimidazole (CDI) as an acylation cyclization agent, with a two-step yield of 90%. However, there is a problem of poor atom economy, and the raw material compound of formula 4 used is restricted by the Chinese patent with publication number CN 105294690B.

[0018]

[0019] Patent WO2012082641 A (2014) discloses that (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester 7c is hydrolyzed and acidified with lithium hydroxide in tetrahydrofuran to obtain a compound of formula 8, which is then activated with isopropyl chloroformate in the presence of triethylamine in dichloromethane, and amidated with concentrated ammonia as an ammonia source to obtain a compound of formula 2. After separation on a silica gel column, the yield of recrystallization is only 79%. This indicates that it contains a large number of impurities generated by side reactions and is not suitable for industrial production.

[0020]

[0021] Patent WO20131B59325 (2013) discloses that the sodium salt of (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 8 is mixed with HOBt-NH3, EDC-HCl and 1-hydroxybenzotriazole in water and stirred for 20 hours, and the yield is only 60%. The yield is low, the atom economy is poor, and it is not suitable for industrial production.

[0022]

[0023] Chinese patent publication number CN106866668 B (2017) discloses a method for synthesizing API from (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester (compound of formula 3c) by a "one-pot" method. The compound of formula 3b is subjected to a carbonyl cyclization reaction with triphosgene in the presence of diisopropylethylamine in tetrahydrofuran to obtain (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (compound of formula 7b), which is then hydrolyzed with aqueous lithium hydroxide solution, acidified to form a carboxylic acid, activated with isopropyl chloroformate in the presence of triethylamine in dichloromethane, and amidated with concentrated aqueous ammonia as an ammonia source at -25 to 5°C to obtain a compound of formula 2, followed by debenzylation and sulfonation to obtain sodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl] sulfate (compound of formula 1), and the total yield of the four-step reaction is 60%. Although this method is simple in process and has an acceptable yield for industrial production, it also has some defects. For example, in the carboxyl activation amidation reaction step, an equivalent amount of organic amine is required as an acid-binding agent and a large excess of ammonia water is required, which will produce a large amount of nitrogen-containing wastewater and put great pressure on the environmental protection. The alkyl chloroformate used is a genotoxic compound and has safety risks.

[0024]

[0025] The Chinese patent (2019) with publication number CN109678856A discloses a method of first hydrolyzing and acidifying the compound of formula 3b in dichloromethane with an aqueous solution of sodium hydroxide or lithium hydroxide to obtain (2S, 5R)-5-benzyloxyaminopiperidine-2-carboxylic acid (compound of formula 10), and then reacting the tetrahydrofuran or dichloromethane solution of the compound of formula 10 with triphosgene in the presence of tributylamine, and amidating with ammonia, ammonia water or ammonia methanol solution to obtain a compound of formula 2. This method completes the carbonyl cyclization reaction and the amidation reaction in one pot, and has the characteristics of high yield, simple operation and low cost. However, this step reaction requires a large excess of tributylamine, triethylamine or diisopropylethylamine as an acid binding agent, which has a large environmental pressure; the use of ammonia has an explosion risk.

[0026]

[0027] According to the second synthetic route, the compound of formula 3 (including methyl ester, ethyl ester and benzyl ester) can be carbonylated and cyclized with triphosgene, and then hydrolyzed and acidified with an inorganic base to obtain the compound of formula 8 with a good yield, which has good atom economy. The subsequent reaction is to activate the carboxyl group by amidation, that is, using an organic base as an acid-binding agent, activating with an alkyl chloroformate, and then amidating with ammonia water, or a solution containing a protic solvent such as ammonia methanol solution, or ammonia gas to obtain the compound of formula 2. Patent US7112592B2 shows that the compound of formula 8 can be quantitatively obtained by activating with n-propyl chloroformate in the presence of triethylamine in dichloromethane and then amidating with concentrated ammonia water; Patent WO2012082641 A (2014) shows that when isopropyl chloroformate is used instead of n-propyl chloroformate, the compound of formula 2 obtained by amidation is separated and recrystallized on a silica gel column and purified with a yield of 79%. Patent CN 105294690A (2016) shows that when pivaloyl chloride is used as the amidation activator, the total yield of the four steps starting from the compound of formula 3 is only 34.5%.

[0028] In summary, in the amidation process, alkyl chloroformate or pivaloyl chloride is used as an activator, and more than 1 equivalent of organic amine is required as an acid-binding agent. A large excess of ammonia gas, ammonia methanol solution or ammonia water will produce a large amount of nitrogen-containing wastewater, which has a great pressure of environmental pollution; due to the sensitivity of the strained urea ring to nucleophilic reagents, the use of ammonia gas, ammonia water, or ammonia methanol solution as an amidation reagent is prone to decarbonylation side reactions (Org. Process Res. Dev. 2016, 20, 1799-1805), resulting in many impurities, difficult purification and low yield; carboxyl activation and amidation need to be carried out at different temperatures, and the operation is complicated. Therefore, how to overcome the above problems in the amidation process has important innovative significance and industrial application value. Summary of the invention

[0029] The invention provides a key intermediate of avibactam sodium and a preparation method thereof. The compound (2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid of formula 8 is used as a raw material. The preparation method generates less waste liquid, is simple to operate, has less by-products, and has high product yield and purity, and is suitable for industrial production.

[0030] The technical solution of the present invention is as follows:

[0031] A method for preparing a key intermediate of avibactam sodium comprises: dissolving a compound of formula 8 ((2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid) in a non-protonic polar organic solvent, and reacting with a carboxyl activator and an ammonia source in the presence of an organic base;

[0032]

[0033] The compound of formula 8 reacts with a carboxyl activator to obtain a compound of formula 9;

[0034]

[0035] The compound of formula 9 reacts with an ammonia source to generate a compound of formula 2 ((2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide);

[0036]

[0037] Wherein, in the compound of formula 9, LG is tert-butyloxycarbonyloxy, n-butyloxycarbonyloxy, iso-butyloxycarbonyloxy, n-propyloxycarbonyloxy, iso-propyloxycarbonyloxy, ethoxycarbonyloxy, methoxycarbonyloxy or benzyloxycarbonyloxy.

[0038] The compound of formula 9 and the compound of formula 2 are both key intermediates of avibactam sodium.

[0039] In the preparation method of the present invention, the compound of formula 8 is activated by carboxyl group to generate the compound of formula 9, and then amidation reaction is performed to obtain the compound of formula 2. The reaction process is shown in the following formula:

[0040]

[0041] Wherein, in the compound of formula 9, LG is tert-butyloxycarbonyloxy, n-butyloxycarbonyloxy, iso-butyloxycarbonyloxy, n-propyloxycarbonyloxy, iso-propyloxycarbonyloxy, ethoxycarbonyloxy, methoxycarbonyloxy or benzyloxycarbonyloxy.

[0042] The strained urea ring in the compound of formula 8 is sensitive to nucleophilic reagents. In the prior art, when ammonia gas, ammonia water, or ammonia methanol solution is used for amidation reaction, a decarbonylation side reaction is easily caused, resulting in a large number of product impurities, difficulty in purification, and low yield. During the research and development process, the inventors found that the strained urea ring in the compound of formula 8 has excellent tolerance in a non-protonic polar organic solvent reaction system, which can significantly reduce the generation of by-products, thereby improving the yield and purity of the product and greatly simplifying the post-processing process.

[0043] The aprotic polar organic solvent is at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane and chloroform.

[0044] Preferably, the aprotic polar organic solvent is at least one of acetonitrile, tetrahydrofuran and N,N-dimethylformamide; most preferably acetonitrile and / or N,N-dimethylformamide.

[0045] The organic base is a nitrogen aromatic compound.

[0046] Preferably, the organic base is at least one of pyridine, substituted pyridine, quinoline, isoquinoline, imidazole, substituted imidazole, benzimidazole, substituted benzimidazole and 1-methylbenzotriazole; further preferably, it is at least one of pyridine, 3-methylpyridine, 2,6-lutidine, 4-(N,N-dimethylamino)pyridine, quinoline, isoquinoline, N-methylimidazole, N-methylbenzimidazole and 1-methylbenzotriazole; further preferably, it is at least one of pyridine, 3-methylpyridine and 4-(N,N-dimethylamino)pyridine; and most preferably, it is pyridine.

[0047] The carboxyl activator is dialkyl dicarbonate.

[0048] Preferably, the carboxyl activator is di-tert-butyl dicarbonate, di-n-butyl dicarbonate, diisobutyl dicarbonate, di-sec-butyl dicarbonate, di-n-propyl dicarbonate, diisopropyl dicarbonate, diethyl dicarbonate, dimethyl dicarbonate, or dibenzyl dicarbonate.

[0049] Further preferably, the carboxyl activator is di-tert-butyl dicarbonate and / or diethyl dicarbonate.

[0050] The ammonia source is ammonium bicarbonate and / or ammonium carbonate.

[0051] To a solution of the compound of formula 8 in an aprotic polar organic solvent, an organic base, a carboxyl activating agent and an ammonia source are added in any order to carry out a one-pot reaction.

[0052] Preferably, the equivalent ratio of the compound of formula 8, the organic base, the carboxyl activator and the ammonia source is 1.0:(0.01-2.0):(1.0-3.0):(1.0-3.0); more preferably, it is 1.0:(0.05-1.0):(1.2-1.8):(1.2-1.8).

[0053] In the amidation process of the present invention, the equivalent ratio of the organic base to the compound of formula 8 can be less than 1, that is, the reaction can be smoothly carried out using a catalytic amount of the organic base, less nitrogen-containing wastewater is generated, and it is more environmentally friendly.

[0054] Most preferably, the equivalent ratio of the compound of formula 8, the organic base, the carboxyl activator and the ammonia source is 1.0:(0.1-0.5):(1.2-1.5):(1.2-1.5).

[0055] Preferably, the mass ratio of the compound of formula 8 to the aprotic polar organic solvent is 1:4-20; more preferably 1:5-8.

[0056] Preferably, the reaction temperature is 0 to 40°C; more preferably 10 to 30°C; most preferably 15 to 25°C.

[0057] The reaction of the present invention can be carried out at room temperature.

[0058] Preferably, the reaction time is 0.1 to 10 h; more preferably 0.5 to 5 h; most preferably 1 to 2 h.

[0059] The present invention also provides a compound of formula 9:

[0060]

[0061] wherein LG is tert-butyloxycarbonyloxy, n-butyloxycarbonyloxy, n-propyloxycarbonyloxy, isopropyloxycarbonyloxy, ethoxycarbonyloxy, methoxycarbonyloxy or benzyloxycarbonyloxy.

[0062] Preferably, the structure of the compound of formula 9 is as shown in formula 9a or formula 9b:

[0063]

[0064] Compared with the prior art, the present invention has the following beneficial effects:

[0065] (1) In the amidation process of the present invention, only a catalytic amount of organic base is used, which results in less pollution and is environmentally friendly;

[0066] (2) The raw materials used in the preparation method of the present invention are easily available and inexpensive, and the production cost is low;

[0067] (3) The reaction of the present invention can be carried out at room temperature, with mild conditions and simple and safe operation;

[0068] (4) The method of the present invention has few by-products, is easy to purify, has a good yield and high purity. The method of the present invention can be scaled up for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 This is the HPLC spectrum of the product before post-treatment in Example 1;

[0070] Figure 2 The HPLC spectrum of the product before post-treatment of Comparative Example 1. DETAILED DESCRIPTION

[0071] The present invention will be further described in detail below in conjunction with specific examples. The inventive method can be implemented by many different combinations, but is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly and comprehensively understood.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0073] Example 1

[0074] Compound 8 (45.0 g, 163 mmol, 1.0 eq.) was dissolved in acetonitrile (600 mL). Pyridine (2.57 g, 32.6 mmol, 0.2 eq.), ammonium bicarbonate (15.4 g, 195 mmol, 1.2 eq.) and di-tert-butyl dicarbonate (42.5 g, 195 mmol, 1.2 eq.) were added in sequence at room temperature. After the addition, the reaction was continued for 1 hour. HPLC detection showed that compound 8 was almost gone and the purity of compound 2 was 97.3% (see Figure 1 , Figure 1 The peak with a retention time between 2 and 3 is the pyridine peak). The solid was removed by filtration and rinsed with a small amount of acetonitrile (45 mL). The filtrate was distilled under reduced pressure to remove the solvent to obtain a solid. The solid was dissolved in dichloromethane (300 mL), washed once with 2N hydrochloric acid (18 mL), and the organic phase was washed with water (2×45 mL), dried over anhydrous sodium sulfate, filtered, and toluene (20 mL) was added to the filtrate. After dichloromethane was evaporated, a solid was precipitated. The solid was filtered, rinsed twice with chlorobutane, and dried by heating under reduced pressure to obtain the product 2, 38.7 g, with a yield of 86% and a purity of 99.2% (HPLC).

[0075] 1 H NMR (400MHz, DMSO) δ7.46-7.44(2H,m),7.15-7.34(4H,m),7.27(1H,s),4.92(2H,dd,J=18.0Hz,J=11.2Hz) ,3.69(1H,d,J=7.2Hz),3.63(1H,s),2.91(2H,s),2.09-2.01(1H,m),1.85-1.81(1H,m),1.72-1.58(2H,m). 13 CNMR(100MHz,DMSO)δ171.8,168.0,136.4,129.4(x2),128.9,128.8(x2),77.4,60.0,57.5,47.2,21.1,18.6.

[0076] Example 2

[0077] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in acetonitrile (30 mL). At room temperature, pyridine (0.25 g, 3.2 mmol, 0.2 eq.), ammonium carbonate (0.94 g, 9.8 mmol, 1.2 eq.), and di-tert-butyl dicarbonate (4.25 g, 19.5 mmol, 1.2 eq.) were added in sequence. After the addition, the reaction was continued for 1 hour. HPLC detected that compound 8 was basically gone, and the purity of compound 2 was 97.5%. The solid was filtered to remove the solid, and the solid was rinsed with a small amount of acetonitrile. The filtrate was distilled under reduced pressure to remove the solvent to obtain a solid. The solid was dissolved in dichloromethane, washed once with 2N hydrochloric acid, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 2, 4.27 g, with a yield of 94.9% and a purity of 99.5%.

[0078] Example 3

[0079] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (30 mL), and 3-methylpyridine (0.30 g, 3.2 mmol, 0.2 eq.), ammonium bicarbonate (1.55 g, 19.5 mmol, 1.2 eq.), and di-tert-butyl dicarbonate (4.25 g, 19.5 mmol, 1.2 eq.) were added in sequence at room temperature. After the addition, the reaction was continued for 4 hours. HPLC detected that compound 8 was basically gone, and compound 2 was 96.4%. It was washed and acidified with 2N hydrochloric acid, and dichloromethane was added to separate the layers. The separated aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed with water twice, and then dried with anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 2, 4.19 g, with a yield of 93.1% and a purity of 99.3%.

[0080] Example 4

[0081] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in acetonitrile (30 mL). At room temperature, pyridine (0.25 g, 32 mmol, 0.2 eq.), ammonium bicarbonate (1.55 g, 19.5 mmol, 1.2 eq.), and diethyl dicarbonate (3.16 g, 19.5 mmol, 1.2 eq.) were added in sequence. After the addition, the reaction was continued for 5 hours. The purity of compound 8 and compound 2 was 96.7% as detected by HPLC. The solid was filtered to remove the solid, and the solid was rinsed with a small amount of acetonitrile. The filtrate was distilled under reduced pressure to remove the solvent to obtain a solid. The solid was dissolved in dichloromethane, washed once with 2N hydrochloric acid, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 2, 4.22 g, with a yield of 93.8% and a purity of 99.5%.

[0082] Example 5

[0083] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (45 mL). At room temperature, pyridine (0.064 g, 0.81 mmol, 0.05 eq.), ammonium bicarbonate (1.55 g, 19.5 mmol, 1.2 eq.), and di-tert-butyl dicarbonate (4.25 g, 19.5 mmol, 1.2 eq.) were added in sequence. After the addition, the reaction was continued for 14 hours. HPLC detected that the remaining compound 8 was 21.1%, the intermediate 9 was 5.9%, and the compound 2 was 68.0%. The solid was filtered out and the solid was rinsed with a small amount of tetrahydrofuran. The filtrate was distilled under reduced pressure to remove the solvent to obtain a solid. The solid was dissolved in dichloromethane, washed once with a small amount of 2N hydrochloric acid, and the organic phase was washed with water again, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 2, 2.79 g, with a yield of 62.5% and a purity of 99.1%.

[0084] Example 6

[0085] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in acetonitrile (45 mL). At room temperature, pyridine (1.29 g, 16.3 mmol, 1.0 eq.), ammonium bicarbonate (1.55 g, 19.5 mmol, 1.2 eq.), and di-tert-butyl dicarbonate (4.25 g, 19.5 mmol, 1.2 eq.) were added in sequence. After the addition, the reaction was continued for 0.5 hours. The purity of compound 8 and compound 2 was 97.1% as detected by HPLC. The solid was filtered out and washed with a small amount of acetonitrile. The filtrate was distilled under reduced pressure to remove the solvent to obtain a solid. The solid was dissolved in dichloromethane, washed with 2N hydrochloric acid, and the water layer was separated. The organic phase was washed with water twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 2, 4.2 g, with a yield of 93.3% and a purity of 99.6%.

[0086] Example 7

[0087] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in acetonitrile (45 mL). At zero degrees, 4-N, N-dimethylpyridine (0.25 g, 3.2 mmol, 0.2 eq.), ammonium carbonate (0.94 g, 9.8 mmol, 1.2 eq.), and di-tert-butyl dicarbonate (4.25 g, 19.5 mmol, 1.2 eq.) were added in sequence. After the addition, the reaction was continued for 3 hours. HPLC detected that compound 8 was basically gone, and the purity of compound 2 was 96.7%. The solid was filtered to remove the solid, and the solid was rinsed with a small amount of acetonitrile. The filtrate was distilled under reduced pressure to remove the solvent to obtain a solid. The solid was dissolved in dichloromethane, then washed with 2N hydrochloric acid, the water layer was separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography to obtain product 2, 4.25 g, with a yield of 94.4% and a purity of 99.5%.

[0088] Comparative Example 1

[0089] Compound 8 (4.5 g, 16.3 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL), cooled to 0°C, triethylamine (2.3 g, 22.8 mmol, 1.4 eq.) and n-butyl chloroformate (2.68 g, 19.6 mmol, 1.2 eq.) were added, stirred for 1 hour, HPLC detection showed that 8 was almost gone, and then 25-28% ammonia water (12.5 mL, 17.3-19.4 mol, 10.6-12 eq.) was added, and the temperature was raised to room temperature and the reaction was continued for 1 hour. HPLC detection showed that the purity of the compound was 87.6% (see Figure 2 ). The organic phase was washed with water (2×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by silica gel column chromatography (n-hexane-ethyl acetate: 1 / 4) to obtain product 2, 3.75 g, with a yield of 83.6% and a purity of 99.3%.

[0090] Example 8 Confirmation of Intermediate 9a

[0091] Compound 8 (10 mg) was dissolved in CDCl3 (0.5 mL), and 0.5 mL of a deuterated chloroform solution of di-tert-butyl dicarbonate (19.0 mg / 1 mL CDCl3) and 0.1 mL of a deuterated chloroform solution of pyridine (6 mg / 1 mL CDCl3) were added. The mixture was shaken at room temperature and scanned. 1 H-NMR and 13 C-NMR spectrum, scanned after 2 hours at room temperature 1 H-NMR and 13 C-NMR spectrum. The spectrum comparison showed that it was intermediate 9a. 1H NMR (400MHz, CDCl3) δ7.43-7.33 (m, 5H), 5.03 and 4.88 (ABq, J = 11.2Hz, 2H), 4.08 (d, 6.8Hz, 1H), 3.31 (d, J = 2.8Hz, 1H), 3 .07(d,J=12.0Hz,1H),2.91(d,J=12.0Hz,1H),2.20-2.11(m,1H),2.11-1.93(m,2H),1.67-1.60(m,1H),1.50(s,9H); 13 C NMR (100MHz, CDCl3) δ 172.2, 167.7, 146.6, 135.5, 129.2 (x 2), 128.7, 128.5 (x 2), 85.1, 78.2, 59.7, 58.0, 47.6, 27.3 (x 9), 20.9, 19.3.

[0092] Example 9 Confirmation of Intermediate 9b

[0093] Compound 8 (10 mg) was dissolved in CDCl3 (0.5 mL), and 0.5 mL of a deuterated chloroform solution of diethyl dicarbonate (14.0 mg / 1 mL CDCl3) and 0.1 mL of a deuterated chloroform solution of pyridine (6 mg / 1 mL CDCl3) were added. The mixture was shaken at room temperature and scanned. 1 H-NMR and 13 C-NMR spectrum, scanned after standing at room temperature for 2 hours 1 H-NMR and 13 C-NMR spectrum. The spectrum comparison showed that it was intermediate 9b. 1 H NMR (400MHz, CDCl3) δ7.44-7.32 (m, 5H), 5.04 and 4.89 (ABq, J = 11.2Hz, 2H), 4.17 (q, J = 7.2Hz, 2H), 4.10-4.06 (m, 1H), 3.3 0(s,1H),3.04(d,J=12.0Hz,1H),2.92(d,J=12.0Hz,1H),2.12-1.99(m,3H),1.70-1.61(m,1H),1.29(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ170.8,168.1,155.1,135.7,129.2(x2),128.7,128.5(x2),78.2,61.6,59.6,58.3,47.4,21.1,19.8,14.1.

[0094] The embodiments described above provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements and equivalent substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of avibactam sodium, characterized in that: include: The compound of formula 8 is dissolved in a non-protonic polar organic solvent, and reacted with a carboxyl activator and an ammonia source in a one-pot process in the presence of an organic base to obtain a key intermediate of avibactam sodium, wherein the key intermediate of avibactam sodium is a compound of formula 2; The reaction mechanism is: the compound of formula 8 reacts with a carboxyl activator to obtain a compound of formula 9; the compound of formula 9 reacts with an ammonia source to generate a compound of formula 2; Wherein, in the compound of formula 9, LG is tert-butyloxycarbonyloxy, n-butyloxycarbonyloxy, iso-butyloxycarbonyloxy, n-propyloxycarbonyloxy, iso-propyloxycarbonyloxy, ethoxycarbonyloxy, methoxycarbonyloxy or benzyloxycarbonyloxy; The carboxyl activator is at least one of di-tert-butyl dicarbonate, di-n-butyl dicarbonate, diisobutyl dicarbonate, di-sec-butyl dicarbonate, di-n-propyl dicarbonate, diisopropyl dicarbonate, diethyl dicarbonate, dimethyl dicarbonate, and dibenzyl dicarbonate; the ammonia source is ammonium bicarbonate and / or ammonium carbonate; The equivalent ratio of the compound of formula 8, the organic base, the carboxyl activating agent and the ammonia source is 1.0: (0.1-1.0): (1.2-1.8): (1.2-1.8).

2. The method for preparing the key intermediate of avibactam sodium according to claim 1, characterized in that: The aprotic polar organic solvent is at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane and chloroform.

3. The method for preparing the key intermediate of avibactam sodium according to claim 2, characterized in that: The aprotic polar organic solvent is at least one of acetonitrile, tetrahydrofuran and N,N-dimethylformamide.

4. The method for preparing the key intermediate of avibactam sodium according to claim 1, characterized in that: The organic base is at least one of pyridine, 3-methylpyridine, 2,6-lutidine, 4-(N,N-dimethylamino)pyridine, quinoline, isoquinoline, imidazole, benzimidazole and 1-methylbenzotriazole.

5. The method for preparing the key intermediate of avibactam sodium according to claim 4, characterized in that: The organic base is at least one of pyridine, 3-methylpyridine and 4-(N,N-dimethylamino)pyridine.

6. The method for preparing the key intermediate of avibactam sodium according to claim 1, characterized in that: Di-tert-butyl dicarbonate and / or diethyl dicarbonate.

7. The method for preparing the key intermediate of avibactam sodium according to claim 1, characterized in that: The equivalent ratio of the compound of formula 8, the organic base, the carboxyl activating agent and the ammonia source is 1.0: (0.1-0.5): (1.2-1.5): (1.2-1.5).

8. The method for preparing the key intermediate of avibactam sodium according to claim 1, characterized in that: The mass ratio of the compound of formula 8 to the aprotic polar organic solvent is 1:4-20.

9. The method for preparing the key intermediate of avibactam sodium according to claim 1, characterized in that: The reaction temperature is 0~40℃; the reaction time is 0.1~10h.

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