A preparation method of an avibactam intermediate

Abstract

The present invention discloses a method for preparing an avibactam intermediate. First, under a strongly alkaline environment, Boc-L-pyroglutamate and trimethylsulfoxide iodide undergo a ring-opening and carbonization reaction to obtain compound 1; then, in the presence of an initiator, the compound reacts with a halogenating agent to obtain compound 2; then, in the presence of a base, the compound reacts with benzyloxyamine hydrochloride to obtain compound 3; compound 3 is deprotected under acidic conditions to obtain compound 4; then, under strongly alkaline conditions, the compound undergoes a ring closure to obtain imine compound 5; finally, under acidic conditions, the compound is reduced with a reducing agent and salted with oxalic acid to obtain (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate oxalate. This synthetic route has the characteristics of not requiring transition metal catalysis, high yield, low cost, and environmental friendliness, meeting the needs of industrial production. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for preparing an avibactam intermediate, namely (2S, 5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate. Background Art

[0002] Avibactam (NXL-104), chemically named [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]sulfate monoester, belongs to the diazabicyclooctanone class of compounds. Avibactam is a novel β-lactamase inhibitor, structurally distinct from classic β-lactamase inhibitors. It exhibits a long-lasting, reversible covalent binding to the enzyme without inducing β-lactamase production, making it the most promising new β-lactamase inhibitor. (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate oxalate (BPO) is a key intermediate in the preparation of avibactam, and its synthesis method holds significant research and application value. However, the intermediate's specific structure complicates its synthesis and hinders industrialization, resulting in its high cost, hindering its widespread medical application.

[0003] Currently, the main synthetic methods for the avibactam intermediate (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate are:

[0004] Patent WO2012172368A discloses a method for synthesizing (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate, as shown in Reaction Scheme 1:

[0005]

[0006] This synthesis method uses N-protected L-pyroglutamate as the starting material. It reacts with trimethylsulfoxide iodide in the presence of a base to undergo ring-opening and carbonization, followed by reaction with benzyloxyamine to form an imine. Acid-catalyzed deprotection, base-catalyzed ring closure, imine reduction, and crystallization with oxalic acid salts yield (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate (BPO). This synthesis method suffers from substrate instability during acidic deprotection, which affects product yield. Furthermore, the final imine reduction step inevitably produces a certain amount of (2S,5S)-5-[(benzyloxy)amino]-piperidine-2-carboxylate (BSS) as a byproduct, accounting for approximately 25%. To remove this cis-isomer impurity, a significant portion of the product is removed during the oxalate crystallization process, resulting in a high residual mother liquor, which significantly affects the yield and productivity of this step.

[0007] The synthesis method of (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate disclosed in U.S. Patent No. US20130296555A1 is shown in Reaction Scheme 2:

[0008]

[0009] This synthetic route also uses N-protected L-pyroglutamate as the starting material and proceeds through ring-opening carbonization, transition-metal-catalyzed cyclization, carbonyl reduction, hydroxyl substitution, removal of the sulfonyl protecting group, and trifluoroacetic acid deprotection to obtain (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate. First, this scheme uses expensive transition-metal-based catalysts in the cyclization step, which is not conducive to cost control. Second, the Mitsunobu reaction requires diethyl azodicarboxylate (DEAD) and triphenylphosphine, which increases costs and waste. Finally, the two deprotection steps require thioglycolic acid and trifluoroacetic acid, which are highly environmentally friendly and polluting. In summary, this route is cumbersome, has high raw material costs, and is highly polluting, making it unsuitable for industrial production. Summary of the Invention

[0010] To address the shortcomings of existing technologies, the present invention provides a novel method for preparing (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate, an intermediate of avibactam. This synthetic route requires no transition metal catalysis, offers high yield, low cost, and is environmentally friendly, meeting the requirements of industrial production.

[0011] The technical solution of the present invention is: a method for preparing an avibactam intermediate (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate, comprising the following steps:

[0012] (1) In a strong alkaline environment, Boc-L-pyroglutamate reacts with trimethylsulfoxide iodide to undergo a ring-opening carbonization reaction to obtain compound 1;

[0013] (2) Compound 1 reacts with a halogenating agent in the presence of an initiator to obtain compound 2;

[0014] (3) Compound 2 reacts with benzyloxyamine hydrochloride in the presence of a base to obtain compound 3;

[0015] (4) Compound 3 is deprotected under acidic conditions to obtain compound 4;

[0016] (5) Compound 4 undergoes cyclization under strong alkaline conditions to give imine compound 5;

[0017] (6) Compound 5 was reduced with a reducing agent under acidic conditions and then precipitated with oxalic acid to obtain (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate oxalate (Compound 6).

[0018] The synthetic route is:

[0019]

[0020] in,

[0021] R is a methyl group, an ethyl group, a tert-butyl group or a benzyl group, and is more preferably an ethyl group.

[0022] X 1 and X 2 is a halogen atom, which may be two identical atoms or a combination of two different atoms; it may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably X 1 and X 2 Both are bromine atoms.

[0023] According to the present invention, preferably, the base used in step (1) is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), preferably potassium tert-butoxide.

[0024] According to the present invention, preferably, the reaction solvent in step (1) is selected from a combination of one or more solvents selected from dichloromethane, ethyl acetate, butyl acetate, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide, and is preferably a mixed solvent of dimethyl sulfoxide and tetrahydrofuran.

[0025] According to the present invention, preferably, the reaction temperature in step (1) is -25 to 25°C, preferably -15 to -10°C.

[0026] According to the present invention, preferably, in step (1), the molar ratio of L-pyroglutamate to trimethylsulfoxide iodide is in the range of 1:1 to 1:2, preferably 1:1.25; the molar ratio of L-pyroglutamate to potassium tert-butoxide is in the range of 1:1 to 1:3, preferably 1:1.1.

[0027] According to the present invention, preferably, the halogenating agent used in step (2) is a combination of one or more reagents selected from chlorine, bromine, elemental iodine, iodine monochloride (ClI), iodine monobromide (BrI), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectfluor), N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), trichloroisocyanuric acid (TCICA), tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBACl), tetrabutylammonium bromide (TBABr), lithium fluoride, potassium fluoride, sodium fluoride, lithium iodide, potassium iodide, sodium iodide, lithium bromide, potassium bromide, sodium bromide, lithium chloride, potassium chloride, and sodium chloride, preferably bromine; the molar ratio of compound 1 to the halogenating agent is in the range of 1:0.9 to 1:2, preferably 1:1.05.

[0028] According to the present invention, preferably, the initiator in step (2) is acetyl peroxide, benzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, preferably azobisisobutyronitrile; the weight ratio of compound 1 to the initiator is in the range of 1:0.005 to 1:0.5, preferably 1:0.01.

[0029] According to the present invention, preferably, the reaction solvent in steps (2) and (4) is selected from a combination of one or more solvents selected from dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichlorothionyl, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, methyl tert-butyl ether, and isopropyl ether, and is preferably ethyl acetate.

[0030] According to the present invention, preferably, the reaction temperature in step (2) is 20-60°C, preferably 30-35°C.

[0031] According to the present invention, preferably, the base used in step (3) is diethylamine, triethylamine, dimethylamine, trimethylamine, pyridine, piperidine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), proton A mixture of one or more bases in (1,8-bisdimethylaminonaphthalene), preferably triethylamine; the weight ratio of compound 2 to triethylamine is in the range of 1:0.9 to 1:4, preferably 1:1.5.

[0032] According to the present invention, preferably, the reaction solvent in step (3) is selected from a mixture of one or more solvents selected from dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, N-methylpyrrolidone, methyl tert-butyl ether, and isopropyl ether, preferably ethyl acetate.

[0033] According to the present invention, preferably, the reaction temperature in step (3) is 20-60°C, preferably 40-45°C.

[0034] According to the present invention, preferably, the molar ratio of compound 2 to benzyloxyamine hydrochloride in step (3) is in the range of 1:0.9 to 1:3, preferably 1:1.2.

[0035] According to the present invention, preferably, the acid used in step (4) is formic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, preferably methanesulfonic acid; the molar ratio of compound 3 to methanesulfonic acid is in the range of 1:0.9 to 1:5, preferably 1:2.

[0036] According to the present invention, preferably, the reaction temperature in step (4) is 0-40°C, preferably 20-25°C.

[0037] According to the present invention, preferably, the base used in step (5) can be an inorganic base such as lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, lithium methoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), potassium hydroxide or sodium hydroxide, or an organic base such as tetramethylguanidine, diethylamine, triethylamine, dimethylamine, trimethylamine, pyridine, piperidine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or proton A composition of one or more bases in (1,8-bis(dimethylaminonaphthalene), preferably an organic strong base tetramethylguanidine; the molar ratio of compound 4 to tetramethylguanidine ranges from 1:0.9 to 1:5, preferably 1:2.5.

[0038] According to the present invention, preferably, the reaction solvent used in step (5) is selected from acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, N-methylpyrrolidone, methyl tert-butyl ether, a mixture of one or more solvents of isopropyl ether, preferably acetonitrile.

[0039] According to the present invention, preferably, the reaction temperature in step (5) is 50-100°C, preferably 80-85°C.

[0040] According to the present invention, preferably, the reducing agent used in step (6) is sodium borohydride, sodium tripropionyloxyborohydride or sodium cyanoborohydride, preferably sodium tripropionyloxyborohydride; the molar ratio of compound 5 to sodium tripropionyloxyborohydride is 1:2 to 1:8, preferably 1:4; the acid used is hydrochloric acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid, preferably sulfuric acid.

[0041] According to the present invention, preferably, the solvent used in step (6) is a combination of one or more solvents selected from water, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, N-methylpyrrolidone, methyl tert-butyl ether, and isopropyl ether, preferably a mixed solvent of water and ethyl acetate.

[0042] According to the present invention, preferably, the reaction temperature in step (6) is -20 to 20°C, preferably -5 to 0°C.

[0043] According to the present invention, preferably, the molar ratio of compound 4 to oxalic acid in step (6) is (0.8-1):(1-2), preferably 1:1.

[0044] Preferably, the preparation method is as follows:

[0045] (1) Under nitrogen protection, potassium tert-butoxide and trimethylsulfoxide iodide were added to a mixed solvent of tetrahydrofuran and dimethyl sulfoxide; the system was cooled to -15 to -10°C, and a tetrahydrofuran solution of Boc-L-pyroglutamate was added dropwise. The mixture was stirred at -15 to -10°C for 2 to 3 hours. The resulting solution was concentrated after post-treatment and recrystallized from methyl tert-butyl ether to obtain compound 1;

[0046] (2) Under nitrogen protection, ethyl acetate was used as a solvent, compound 1 and an initiator, azobisisobutyronitrile, bromine was added dropwise to the reaction system, and the temperature was raised to 30-35°C for 6-8 hours; after post-treatment, an ethyl acetate solution of compound 2 was obtained;

[0047] (3) Adding benzyloxyamine hydrochloride to the ethyl acetate solution of compound 2; then adding triethylamine and heating the reaction system to 40-45° C. for 6-8 hours; after post-treatment, the solution of compound 3 is obtained, which is concentrated and then recrystallized by adding methyl tert-butyl ether to obtain compound 3;

[0048] (4) Compound 3 was dissolved in ethyl acetate, cooled to 0-5°C, and methanesulfonic acid was added dropwise; the temperature was then raised to 20-25°C and reacted for 4-6 hours; after post-treatment, the mixture was recrystallized from methyl tert-butyl ether to obtain compound 4;

[0049] (5) Compound 4 is dissolved in acetonitrile as a solvent; tetramethylguanidine is added and the temperature is raised to 80-85° C., and the reaction is kept warm for 8-10 hours; after post-treatment and concentration, a concentrated ethyl acetate solution of compound 5 is obtained;

[0050] (6) The concentrated ethyl acetate solution of compound 5 was cooled to -5 to 5°C, sulfuric acid was added, and the reducing agent sodium tripropoxyborohydride ethyl acetate solution was slowly added under temperature control. The reaction was carried out at -5 to 0°C and post-treated. Oxalic acid was added to the ethyl acetate / methanol system to obtain compound 6 for crystallization.

[0051] Furthermore, the post-treatment of step (1) is as follows: controlling the temperature at 0-5°C and adding the aqueous ammonium chloride solution dropwise to the reaction system, and extracting with ethyl acetate and washing with salt after the addition is completed.

[0052] Furthermore, the post-treatment of step (2) is as follows: cooling the system to 0-5°C, adding a pre-cooled 5% sodium thiosulfate aqueous solution and stirring, and then extracting with ethyl acetate and washing with salt.

[0053] Furthermore, the post-treatment of step (3) is as follows: cooling to 15-20° C., adding saturated sodium chloride solution, stirring, standing to separate the liquids, and concentrating the organic phase.

[0054] Furthermore, the post-treatment of step (4) is as follows: cooling the system to 0-5°C, adding sodium carbonate solution, stirring, standing to separate the liquids, and concentrating the organic phase.

[0055] Furthermore, the post-treatment of step (5) is as follows: concentrating the reaction system, adding ethyl acetate and water to the concentrated residue, stirring, adding solid sodium chloride, continuing stirring, standing, separating the liquids, and washing the organic phase with salt.

[0056] Furthermore, the post-treatment of step (6) is as follows: adding water to quench the reaction, and adjusting the pH to 7.0-7.5 with aqueous ammonia; controlling the temperature at 0-5°C to stir the mixed liquid, let it stand, separate the layers, and wash the organic phase with salt and concentrate it.

[0057] The technical features and beneficial effects of the present invention are as follows:

[0058] (1) The present invention uses cheap and readily available Boc-L-pyroglutamate as a starting material, and the reagents used in each step are very conventional. Therefore, the scheme can prepare (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate at a low cost;

[0059] (2) The process of the present invention does not involve a transition metal catalysis step, so the prepared (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate will not be contaminated by heavy metals;

[0060] (3) In the final reduction step of the present invention, the amount of the cis-isomer impurity (2S,5S)-5-[(benzyloxy)amino]-piperidine-2-carboxylate (BSS) generated is ≤3.0%. A single isomer product can be obtained by forming oxalate crystals, with low mother liquor residue and high yield.

[0061] (4) The reaction conditions of the present invention are mild, each step of the reaction is classic and easy to operate, low cost, environmentally friendly, and meet the needs of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is a liquid phase spectrum of the product obtained by repeating the process of Example 1g of patent WO2012172368;

[0063] Figure 2 This is the liquid phase spectrum of the product compound 6 obtained in Example 6 of the present invention. DETAILED DESCRIPTION

[0064] The present invention is further described by way of the following examples, which are not intended to limit the present invention in any way. Any modifications or variations that are readily accomplished by one of ordinary skill in the art will fall within the scope of the present invention.

[0065] Example 1: Synthesis of (S)-ethyl 2-[(tert-butoxycarbonyl)amino]-6-(dimethylsulfinyl)-5-oxohexanoate (Compound 1):

[0066]

[0067] Under nitrogen, 106.9 g of trimethylsulfoxide iodide and 48.0 g of t-BuOK were added to 350 ml of THF at 25°C, followed by 500 ml of DMSO. The mixture was stirred at room temperature for 1 hour, then cooled to -15 to -10°C. A mixed solution consisting of 100.0 g of Boc-L-pyroglutamic acid ethyl ester and 200 ml of THF was slowly added dropwise. The pipe system was then flushed with 50 ml of tetrahydrofuran. The mixture was stirred at -15 to -10°C for 2 to 3 hours until the residual starting material was ≤ 2.0%. Then, 700 ml of a 20% aqueous ammonium chloride solution was added dropwise to the reaction system at a temperature of 0 to 5°C. After the addition was complete, 1000 ml of ethyl acetate was added. After stirring for 15 minutes, the mixture was allowed to stand for 10 minutes. The organic phase was transferred to a storage tank for storage. 500 ml of ethyl acetate was added to the aqueous phase, stirred for 15 minutes, allowed to stand for 10 minutes, and the aqueous phase was separated and stored as waste liquid. The first and second organic phases were combined, 300 ml of 10 wt% sodium chloride solution was added, and the mixture was stirred for 15 minutes. The mixture was allowed to stand for 10 minutes, and the aqueous phase was separated and stored as waste liquid. The organic phase was concentrated to 250.0-300.0 g at 20-25°C. 200 ml of methyl tert-butyl ether and 0.3 g of compound 1 seed crystals were added, and the mixture was stirred and crystallized at 25°C for 2 hours. 1000 ml of methyl tert-butyl ether was added dropwise over 30 minutes, stirred at 25°C for 1 hour, and then cooled to 0-5°C and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with 300 ml of methyl tert-butyl ether. The solid was removed and vacuum dried at 25-30°C for 8 hours until the moisture content was ≤0.1%. The solid yield was 120 g, off-white in color, with a yield of 88.2% and a purity of ≥98.0% as determined by HPLC. The solid was stored in a refrigerator at -25°C until further use.

[0068] Example 2: Synthesis of (S)-2-[(tert-Butoxycarbonyl)amino]-6,6-dibromo-5-oxohexanoic acid ethyl ester (Compound 2):

[0069]

[0070] Under nitrogen protection, 480 ml of ethyl acetate was added to the reaction flask at 25 ° C, followed by 80.0 g of compound 1 and 0.8 g of azobisisobutyronitrile. The system was cooled to 0-5 ° C, and 38.5 g of bromine was added dropwise over 30 min. After the addition was complete, the reaction was heated to 30-35 ° C for 6-8 h. After HPLC analysis showed that the residual compound 1 was ≤1.0%, the system was cooled to 0-5 ° C, 300 ml of pre-cooled 5% sodium thiosulfate aqueous solution was added, stirred for 15 min, and allowed to stand for 10 min. The liquid was separated and the organic phase was transferred to a storage tank for storage. 150 ml of ethyl acetate was added to the aqueous phase, stirred for 15 min, and allowed to stand for 10 min. The liquid was separated and the aqueous phase was separated and stored as waste liquid. The organic phase was separated and combined with the first organic phase, 100 ml of saturated sodium chloride solution was added, stirred for 15 min, and allowed to stand for 10 min. The liquid was separated and the aqueous phase was separated and stored as waste liquid. The purity of the organic phase was ≥93.0%, and the next step of reaction was carried out directly without further treatment.

[0071] Example 3: Synthesis of (S)-2-[(tert-Butoxycarbonyl)amino]-6,6-dibromo-5-(benzyloxyimino)hexanoic acid ethyl ester (Compound 3):

[0072]

[0073] The ethyl acetate solution of compound 2 was cooled to 5-10°C, 43.9 g of benzyloxyamine hydrochloride was added, the temperature was controlled below 10°C, and 34.8 g of TEA was added dropwise over 30 minutes. After the addition is complete, the temperature is raised to 40-45°C and stirred for 6-8h. After the residual compound 2 is ≤1.0% by HPLC, the temperature is lowered to 15-20°C, 320ml of saturated sodium chloride solution is added, stirred for 15min, allowed to stand for 10min, the liquid is separated, the aqueous phase is separated and stored as waste liquid, the organic phase is transferred and concentrated to 150.0-170.0g at 20-25°C, the temperature is controlled at 18-22°C, 150ml of methyl tert-butyl ether and 0.3g of seed crystals are added, the crystal is kept warm for 2h, 700ml of methyl tert-butyl ether is added dropwise for 30min, and the crystal is kept warm for 2h after the addition is complete. The temperature is lowered to 0-5°C, the crystal is kept warm for 2h, filtered, and the filter cake is washed three times with 160ml of methyl tert-butyl ether. The solid is taken out and dried in vacuo at 30-40°C for 8h-12h to a moisture content of ≤0.1%. The solid material was 89.1 g, light yellow in color, with a two-step yield of 72.6% and a purity of ≥98.0% as determined by HPLC. The solid was stored in a -25°C refrigerator for later use.

[0074] Example 4: Synthesis of (S)-5-(benzyloxyimino)-6,6-dibromo-2-aminohexanoic acid ethyl ester (Compound 4):

[0075]

[0076] At 25°C, 480 ml of ethyl acetate and 60.0 g of compound 3 were added to the reaction flask, the temperature was lowered to 5°C, and 21.6 g of methanesulfonic acid was added dropwise while maintaining the temperature below 10°C. The addition was completed over about 30 minutes. After the addition is completed, the temperature is raised to 20-25°C and stirred for reaction for 4-6 hours. After HPLC detection of the residual compound 3 is ≤1.0%, the temperature is lowered to 0-5°C, 200 ml of 7% w / w sodium carbonate solution is added, stirred for 15 minutes, allowed to stand for 10 minutes, and the liquid is separated. The aqueous phase is separated and stored as waste liquid. The organic phase is concentrated to 95.0-105.0 g at a temperature of 20-25°C, 100 ml of methyl tert-butyl ether and 0.3 g of seed crystals are added at a temperature of 20-25°C, and the crystals are grown for 1.5-2 hours. 500 ml of methyl tert-butyl ether is added dropwise, and the crystals are grown at a temperature of 20-25°C for 2 hours. After filtering, the filter cake is washed with 100 ml of methyl tert-butyl ether, the solid is taken out, and dried in vacuo at 30-40°C for 8-12 hours to a moisture content of ≤0.1%. The solid material was 44.9 g, a brown solid, with a yield of 92.0% and a purity of ≥97.0% as determined by HPLC. The solid was stored in a -25°C refrigerator for later use.

[0077] Example 5: Synthesis of (S)-5-(benzyloxyimino)-2,3,4,5-tetrahydropyridine-2-carboxylic acid ethyl ester (Compound 5):

[0078]

[0079] Under nitrogen protection, 160ml of acetonitrile and 40.0g of compound 4 were added to the reaction flask at 25°C. The system was cooled to 0-5°C and 26.4g of tetramethylguanidine was added dropwise for 30min. After the addition was complete, the temperature was raised to 80-85°C and the reaction was allowed to proceed for 8-10h. After HPLC analysis showed that the residual amount of compound 4 was ≤2.0%, the reaction system was transferred to a rotary evaporator and concentrated to 72.0-80.0g at 20-25°C. 160ml of ethyl acetate and 160ml of water were added to the concentrated residue, stirred for 15min, and then 16.0g of solid sodium chloride was added. The mixture was stirred for 15min, allowed to stand for 10min, and the organic phase was transferred to a storage tank for storage. The aqueous phase was separated and 100ml of ethyl acetate was added and stirred for 15min. The mixture was allowed to stand for 10min, and the aqueous phase was separated and stored as waste liquid. The organic phase was separated and combined with the first separated organic phase, 400 ml of 20% sodium chloride solution was added, stirred for 15 minutes, allowed to stand for 10 minutes, and layers were separated. The aqueous phase was separated and stored as waste liquid, and the organic phase was concentrated to 180.0 g to 200.0 g at 20-25 ° C for use.

[0080] Example 6: Synthesis of (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylic acid ethyl ester oxalate (Compound 6):

[0081]

[0082] At 25°C, add 13.9g of sodium borohydride to 360ml of ethyl acetate. Cool the system to 0-5°C and dropwise add 81.8g of propionic acid. After the addition is complete, stir the reaction at 0-5°C for 8-10 hours. Set aside the resulting solution (sodium tripropionyloxyborohydride solution).

[0083] In another reaction flask, cool the ethyl acetate solution of Compound 5 to 0-5°C and mix with 92.0g of concentrated sulfuric acid. Continue cooling to -5-0°C, then add the sodium tripropionyloxyborohydride solution obtained above dropwise to the reaction system. Stir and react at -5-0°C until the residual amount of Compound 5 is ≤2.0%. At -5-0°C, add 400ml of water to quench the reaction, and adjust the pH to 7.0-7.5 with aqueous ammonia. Stir the mixture at 0-5°C for 15 minutes, let it stand for 10 minutes, and allow the layers to separate. Transfer the organic phase to a transfer tank for storage. Add 200ml of ethyl acetate to the aqueous phase, stir for 15 minutes, let it stand for 10 minutes, separate the layers, and store the aqueous phase as waste. Combine the organic phase with the first separated organic phase, add 400ml of 10% sodium chloride solution, stir for 15 minutes, let it stand for 10 minutes, separate the layers, and store the aqueous phase as waste. Concentrate the organic phase at 20-25°C to 70-75g. Control the temperature at 20-25°C, and add the concentrated liquid dropwise to a solution of 11.6g of oxalic acid dihydrate dissolved in 240ml of methanol for 4 hours. After the addition is complete, control the temperature at 20-25°C to grow the crystals for 2 hours, then cool to 0-5°C and grow the crystals for 2 hours. Filter, wash the filter cake with a mixed solvent of 60ml of ethyl acetate: methanol (3:1), and then wash with 40ml of ethyl acetate. Take out the solid and vacuum dry it at 30-40°C for 8h-12h until the moisture content is ≤0.1%. 21.2g of solid material is collected, which is an off-white solid with a two-step yield of 62.7%. The purity detected by HPLC is ≥99.0%, and it is stored in a refrigerator at -25°C. The liquid phase spectrum of the obtained product compound 6 is as follows Figure 2 As shown, it can be seen that the liquid phase spectrum of the product obtained by the process of Example 1g of the repeated patent WO2012172368 ( Figure 1 ) are consistent, proving that the product is generated.

Claims

1. A method for preparing an avibactam intermediate, wherein the avibactam intermediate is (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate; characterized in that: The preparation method comprises the following steps: (1) In a strongly alkaline environment, Boc-L-pyroglutamate reacts with trimethylsulfoxide iodide to undergo a ring-opening carbonization reaction to obtain compound 1; the base used in the strongly alkaline environment is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, lithium diisopropylamide or lithium hexamethyldisilazide; (2) Compound 1 reacts with a halogenating agent in the presence of an initiator to obtain compound 2; (3) Compound 2 reacts with benzyloxyamine hydrochloride in the presence of a base to obtain compound 3; (4) Compound 3 is deprotected under acidic conditions to obtain compound 4; (5) Compound 4 undergoes cyclization under strong alkaline conditions to obtain imine compound 5; the base used in the strong alkaline conditions is tetramethylguanidine; (6) Compound 5 was reduced with a reducing agent under acidic conditions and then precipitated with oxalic acid to obtain (2S,5R)-5-[(benzyloxy)amino]-piperidine-2-carboxylate oxalate; in, R is methyl, ethyl, tert-butyl or benzyl; X 1 and X 2 It is a combination of two identical atoms or two different atoms; it is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

2. The preparation method according to claim 1, wherein Said is X 1 and X 2 Both are bromine atoms; R is ethyl.

3. The preparation method according to claim 1, wherein In step (1), the reaction solvent is selected from a combination of one or more solvents selected from dichloromethane, ethyl acetate, butyl acetate, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide; and the reaction temperature is -25 to 25°C.

4. The preparation method according to claim 1, wherein The halogenating agent used in step (2) is a combination of one or more of chlorine, bromine, elemental iodine, iodine monochloride, and iodine monobromide; the initiator is acetyl peroxide, benzoyl peroxide, azobisisobutyronitrile, or azobisisoheptanenitrile; and the reaction temperature in step (2) is 20 to 60°C.

5. The preparation method according to claim 1, wherein The reaction solvent in steps (2) and (4) is selected from a combination of one or more solvents selected from dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichlorothionyl, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, methyl tert-butyl ether, and isopropyl ether.

6. The preparation method according to claim 1, wherein: The base used in step (3) is a mixture of one or more bases selected from diethylamine, triethylamine, dimethylamine, trimethylamine, pyridine, piperidine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, and 1,8-bisdimethylaminonaphthalene; the reaction solvent in step (3) is a mixture of one or more solvents selected from dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, N-methylpyrrolidone, methyl tert-butyl ether, and isopropyl ether; and the reaction temperature in step (3) is 20 to 60°C.

7. The preparation method according to claim 1, wherein: The acid used in the acidic condition in step (4) is any one of formic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid; and the reaction temperature is 0-40°C.

8. The preparation method according to claim 1, wherein The reaction solvent used in step (5) is selected from a mixture of one or more solvents selected from acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, N-methylpyrrolidone, methyl tert-butyl ether, and isopropyl ether; the reaction temperature is 50-100°C.

9. The preparation method according to claim 1, wherein: The reducing agent used in step (6) is sodium borohydride, sodium tripropionyloxyborohydride or sodium cyanoborohydride; the acid used in the acidic condition is hydrochloric acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid; the solvent used in step (6) is a combination of one or more solvents selected from water, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, butyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, N-methylpyrrolidone, methyl tert-butyl ether and isopropyl ether; and the reaction temperature is -20 to 20°C.

10. The preparation method according to any one of claims 1 to 9, characterized in that: (1) Under nitrogen protection, potassium tert-butoxide and trimethylsulfoxide iodide were added to a mixed solvent of tetrahydrofuran and dimethyl sulfoxide; the system was cooled to -15 to -10°C, and a tetrahydrofuran solution of Boc-L-pyroglutamate was added dropwise. The mixture was stirred at -15 to -10°C for 2 to 3 hours. The resulting solution was concentrated after post-treatment and recrystallized from methyl tert-butyl ether to obtain compound 1; (2) Under nitrogen protection, ethyl acetate was used as a solvent, compound 1 and an initiator, azobisisobutyronitrile, bromine was added dropwise to the reaction system, and the temperature was raised to 30-35°C for 6-8 hours; after post-treatment, an ethyl acetate solution of compound 2 was obtained; (3) Adding benzyloxyamine hydrochloride to the ethyl acetate solution of compound 2; then adding triethylamine and heating the reaction system to 40-45° C. for 6-8 hours; after post-treatment, the solution of compound 3 is obtained, which is concentrated and then recrystallized by adding methyl tert-butyl ether to obtain compound 3; (4) Compound 3 was dissolved in ethyl acetate, cooled to 0-5°C, and methanesulfonic acid was added dropwise; the temperature was then raised to 20-25°C and reacted for 4-6 hours; after post-treatment, the mixture was recrystallized from methyl tert-butyl ether to obtain compound 4; (5) using acetonitrile as a solvent and dissolving compound 4 therein; Tetramethylguanidine was added and the temperature was raised to 80-85° C., and the reaction was kept warm for 8-10 hours; after post-treatment and concentration, a concentrated ethyl acetate solution of compound 5 was obtained; (6) The concentrated ethyl acetate solution of compound 5 was cooled to -5 to 5°C, sulfuric acid was added, and the reducing agent sodium tripropionyloxyborohydride ethyl acetate solution was slowly added at -5 to 0°C under temperature control. After post-treatment, oxalic acid was added to the ethyl acetate / methanol system to obtain compound 6 for crystallization.

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