A process for the preparation of chiral alpha-hydroxy-amidoxime ethers

Abstract

This invention proposes a method for preparing chiral α-hydroxy-mercapto-oxime ethers, belonging to the field of organic synthesis technology. The method comprises: S1. protecting the hydroxyl group of chiral α-hydroxypropionamide with a protecting group; S2. reacting the chiral α-protecting group-propionamide sequentially with an oxonium salt donor and an alkoxyamine hydrochloride to obtain chiral 1-[(E)-alkoxynitro]-α-protecting-propyl-1-amine; S3. removing the protecting group from the chiral 1-[(E)-alkoxynitro]-α-protecting-propyl-1-amine to obtain the product. This invention aims to overcome the core defects of existing processes, such as low yield, high impurity content, high reagent safety and environmental risks, high pyridine consumption, and cumbersome operation, and to develop a new process for synthesizing chiral α-hydroxy-mercapto-oxime ethers with high yield, high purity, low cost, high safety, and suitability for industrial scale-up.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing chiral α-hydroxy-mercaptooxime ethers. Background Technology

[0002] The core value of chiral oxime ethers lies in the fact that their NO bonds can endow drug molecules with unique pharmacokinetic properties. For example, oxime ethers can be converted into chiral hydroxylamine (CN-OH) through asymmetric hydrogenation. The latter is a key building block of many drugs and bioactive compounds. Axial chiral anthrone oxime ethers can be converted into dibenzo-azolones with central chirality through Beckmann rearrangement ring expansion. This skeleton is widely present in bioactive molecules, including enhancing metabolic stability and improving target binding affinity, and has a wide range of applications.

[0003] Existing technologies employ a four-step synthetic route to prepare (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol. Starting with L-lactic acid, the product is obtained through a four-step reaction involving hydroxytriisopropylsilyl (TIPS) protection, phosphorus pentasulfide oxidation, high-temperature methoxyamineization in pyridine solvent, and deprotection with tetrabutylammonium fluoride (TBAF). Each step requires independent post-processing, concentration, and purification. The core conversion step employs an oxidation-oxime stepwise process, using high-risk oxidizing agents and a large amount of pyridine as the reaction solvent.

[0004] This synthesis method has the following problems:

[0005] 1. The overall yield is extremely low, only 23.8%, resulting in significant raw material losses, high industrial production costs, and poor economic efficiency;

[0006] 2. Poor impurity control: Methoxyamine disubstituted impurities account for as high as 39.9% of the product GC, and the crude product purity is only 40.4%. Multiple column chromatography purifications are required, resulting in large purification losses and making it difficult to achieve stable industrial production.

[0007] 3. High safety and environmental risks: S5P2 reagent is used as an oxidant. This reagent is flammable and explosive, and poses a risk of environmental pollution. Furthermore, the post-treatment requires multiple filtrations and washings, which is cumbersome and generates a large amount of waste.

[0008] 4. High solvent cost and difficult post-processing: Using pyridine as a reaction solvent results in large quantities and high cost. Furthermore, pyridine has poor water solubility, making post-processing separation difficult, resulting in high solvent loss and high wastewater treatment costs.

[0009] 5. The operation is cumbersome and the production efficiency is low. Each reaction step is operated independently. The intermediate products need to be concentrated, transferred and purified multiple times, which can easily lead to product degradation. The production cycle is long and the operation safety risks are high. Summary of the Invention

[0010] The purpose of this invention is to propose a method for preparing chiral α-hydroxy-mercaptooxime ethers, overcoming the core defects of existing processes such as low yield, high impurity content, high reagent safety and environmental risks, high pyridine consumption, and cumbersome operation, and developing a new process for synthesizing chiral α-hydroxy-mercaptooxime ethers with high yield, high purity, low cost, high safety, and suitability for industrial scale-up.

[0011] The technical solution of this invention is implemented as follows:

[0012] This invention provides a method for preparing the above-mentioned chiral α-hydroxy-metamine oxime ether, comprising the following steps:

[0013] S1. By protecting the hydroxyl group of chiral α-hydroxypropionamide with a protecting group, a chiral α-protecting group-propionamide is prepared. The structural formula of the chiral α-hydroxypropionamide is as follows: The structural formula of the chiral α-protecting group-propionamide is as follows; ;

[0014] S2. Chiral α-protecting propionamide was reacted sequentially with an oxonium salt donor and an alkoxyamine hydrochloride to prepare chiral 1-[(E)-alkoxynitro]-α-protecting propan-1-amine, with the following structural formula: ;

[0015] S3. Remove the protecting group from the chiral 1-[(E)-alkoxynitro]-α-protecting group-propane-1-amine to obtain the product.

[0016] As a further improvement of the present invention, R1 and R2 are each independently C1-C 12 alkyl chain.

[0017] As a further improvement of the present invention, both R1 and R2 are CH3.

[0018] As a further improvement of the present invention, the protecting group is a silane protecting group; the chiral α-hydroxypropionamide is L-lactamide; the alkoxyamine hydrochloride is methoxyamine hydrochloride; and the oxonium salt donor is trimethyloxonium tetrafluoroboric acid or oxonium salt-supported microspheres.

[0019] Trimethyloxonium tetrafluoroboric acid (TOCA) suffers from drawbacks such as high cost, extreme sensitivity to moisture, production of dimethyl ether as a byproduct, and poor atom economy. During the reaction process, TOCA is typically required in excess, significantly increasing the cost of the raw materials. Therefore, this invention designs and prepares TOCA-loaded microspheres, which offer advantages such as recyclability, easy separation, suitability for continuous flow, and improved atom economy. This reduces the amount of TOCA used, lowering costs. Furthermore, after the TOCA-loaded microspheres participate in the reaction, they can be separated and reloaded with TOCA for repeated reactions, thus greatly improving the utilization rate of the microspheres.

[0020] Preferably, the method for preparing the oxyonium salt-loaded microspheres is as follows:

[0021] T1. Add Fe3O4 NPs to ethanol, add alkyl orthosilicate, stir and mix evenly, add water, pore-forming agent and ammonia, stir to react, separate with a magnet, wash, dry and calcine to obtain mesoporous magnetic SiO2 microspheres;

[0022] Mesoporous magnetic SiO2 microspheres have a good specific surface area and mesoporous channels, which is beneficial for subsequent loading of trimethyloxonium tetrafluoroboric acid. At the same time, the encapsulation of Fe3O4 NPs inside the microspheres makes the microspheres magnetic, which facilitates separation by magnets and simplifies the separation steps of the microspheres.

[0023] T2. Mesoporous magnetic SiO2 microspheres were added to ethanol, followed by 3-chloropropyltrimethoxysilane and ammonia. The mixture was heated under reflux with stirring, separated by a magnet, washed, and dried to obtain chlorine-modified mesoporous magnetic SiO2 microspheres. A schematic diagram of the synthesis is shown below.

[0024] ;

[0025] T3. Chlorine-modified mesoporous magnetic SiO2 microspheres and N-methylimidazole were added to chloroform, heated under an inert atmosphere and refluxed, separated by a magnet, washed, and dried to obtain quaternary ammonium chloride-modified magnetic microspheres.

[0026] In this reaction, alkyl chlorides react with N-methylimidazole in an SN2 reaction to generate imidazolium chloride.

[0027] T4. Quaternary ammonium chloride-modified magnetic microspheres were added to ethanol, followed by tetrafluoroborate and anion exchange resin. The mixture was stirred at room temperature, separated by magnets, washed, and the final wash solution was tested to ensure it contained no Cl. - Modified mesoporous magnetic SiO2 microspheres were prepared.

[0028] In this reaction, quaternary ammonium chloride-modified magnetic microspheres undergo an ion exchange reaction with tetrafluoroborate. A small amount of strongly basic anion exchange resin is added, allowing the exchanged Cl- to be adsorbed in situ. - This pushes the balance to the right, and finally, after testing, ensures that Cl... - Completely swapped into BF4 - .

[0029] T5. Trimethyloxonium tetrafluoroboric acid and modified mesoporous magnetic SiO2 microspheres were mixed and added to dichloromethane. The mixture was stirred at room temperature to react and the solvent was evaporated to obtain oxonium salt-loaded microspheres.

[0030] In this reaction, trimethyloxonium tetrafluoroboric acid is physically impregnated and confined within the mesoporous channels, retained by hydrogen bonds and van der Waals forces on the pore walls. The modified mesoporous magnetic SiO2 microspheres contain a large number of Si-OH groups on their pore walls, which can react with BF4. - The C2-H (acidic hydrogen) of the imidazolium cation can form a CH···O hydrogen bond with the oxygen of the oxonium ion. At the same time, the confinement effect of the pore space prevents the free diffusion of ion pairs.

[0031] Preferably, the average particle size of the Fe3O4 NPs in step T1 is 100-200 nm, the mass ratio of the Fe3O4 NPs, alkyl orthosilicate, pore-forming agent and ammonia is (5-10):(10-12):(2-3):(3-5), the pore-forming agent is hexadecyltrimethylammonium bromide or hexadecyltrimethylammonium chloride, the alkyl orthosilicate is methyl orthosilicate or ethyl orthosilicate, the stirring reaction time is 12-15 h, and the calcination temperature is 450-550 °C for 1-3 h.

[0032] Preferably, in step T2, the mass ratio of the mesoporous magnetic SiO2 microspheres to 3-chloropropyltrimethoxysilane is (1-3):(3-5), and the heating, reflux, and stirring reaction time is 3-5 hours.

[0033] Preferably, in step T3, the mass ratio of the chlorine-modified mesoporous magnetic SiO2 microspheres to N-methylimidazole is (5-10):(2-4), and the heating and reflux reaction time is 20-28 h.

[0034] Preferably, in step T4, the tetrafluoroborate is sodium tetrafluoroborate or potassium tetrafluoroborate; the mass ratio of the quaternary ammonium chloride-modified magnetic microspheres to the tetrafluoroborate is 10:(5-10); the anion exchange resin, such as D201 or IRA-400, is added at 10-20 wt% of the quaternary ammonium chloride-modified magnetic microspheres; the reaction time at room temperature with stirring is 12-24 h; and the final washing solution is tested to ensure it does not contain Cl. - The method involves adding AgNO3 solution (0.1 mol / L). If no white precipitate (AgCl) forms, it indicates that Cl... - It has been completely washed.

[0035] Preferably, the mass ratio of trimethyloxonium tetrafluoroboric acid and modified mesoporous magnetic SiO2 microspheres in step T5 is (3-4):10, and the stirring reaction time at room temperature is 1-2 hours.

[0036] As a further improvement of the present invention, the molar ratio of the chiral α-protecting group propionamide, trimethyloxonium tetrafluoroboric acid, and alkoxyamine hydrochloride is 1:(1.5-2):(5-6).

[0037] As a further improvement of the present invention, in step S2, the reaction conditions with the oxonium salt donor are an inert gas atmosphere, a temperature of 15-25°C, and a time of 12-20 hours.

[0038] As a further improvement of the present invention, in step S2, the reaction conditions with alkoxyamine hydrochloride are an inert gas atmosphere, the addition of an acid-binding agent, a temperature of 0-10°C, and a reaction time of 1-2 hours.

[0039] As a further improvement of the present invention, the acid-binding agent is pyridine or triethylamine.

[0040] As a further improvement of the present invention, in step S3, when the protecting group is triisopropylsilyl, the reagent used to remove the protecting group is tetrabutylammonium fluoride.

[0041] As a further improvement of the present invention, in step S3, when the protecting group is tert-butyldimethylsilyl, the reagent used to remove the protecting group is hydrochloric acid.

[0042] The present invention has the following beneficial effects:

[0043] 1. A novel two-step methylation-methoxyamination reaction pathway was developed, overturning the existing stepwise oxidation-oxime process: the stepwise reaction of S5P2 oxidation and high-temperature oxime in the existing process was abandoned. Trimethyloxonium tetrafluoroboric acid was used to first activate the amide by methylation, and then the reaction was directly carried out by low-temperature methoxyamination. The oxidation side reaction was avoided from the reaction mechanism, and the conversion efficiency was greatly improved.

[0044] 2. Replace the high-risk S5P2 oxidizing agent with a safe and stable methylating agent: replace the flammable, explosive and environmentally risky S5P2 agent with trimethyloxonium tetrafluoroboric acid, completely eliminating the safety and environmental hazards of the oxidation step, while eliminating the post-processing steps of the oxidation reaction and greatly simplifying the operation process.

[0045] 3. Low-temperature equivalent pyridine reaction system, completely eliminating disubstituted impurities: The existing process of high-temperature pyridine solvent reaction at 65-75℃ is optimized to low-temperature equivalent pyridine reaction at 0-10℃. The amount of pyridine used is reduced from solvent level to 6.0 eq, which not only significantly reduces the cost of raw materials and waste treatment, but also fundamentally inhibits the disubstituted side reaction of methoxyamine. The disubstituted impurities are reduced from 39.9% to undetectable levels.

[0046] 4. Multi-step reaction continuous addition process, which greatly improves production efficiency and yield: It realizes the direct addition of the next step after hydroxyl protection and the two-step continuous addition of methylation-methoxyamination, which eliminates the need for multiple concentration, separation and purification steps of intermediate products, reduces degradation loss during product transfer, and shortens the production cycle. The yield of the core two steps is increased from less than 30% in the existing process to 74.5%, and the overall yield is increased to more than 45%.

[0047] 5. Optimize the final product purification process to solve the column blockage problem caused by TBAF residue, and improve the purification yield and product quality stability. Attached Figure Description

[0048] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0049] Figure 1 SEM image of the oxygen-loaded oxonium salt microspheres prepared in Example 1.

[0050] Figure 2 The hydrogen spectrum of (2R)-1-amino-1-[(E)-methoxynimidyl]prop-2-ol prepared in Example 1.

[0051] Figure 3 The gas chromatogram of the product of step S1 in Example 7;

[0052] Figure 4 The central control gas chromatogram of the product of step S2 in Example 7;

[0053] Figure 5 The gas chromatogram of the product of step S2 in Example 7;

[0054] Figure 6 This is a gas chromatogram of the product from step S3 in Example 7. Detailed Implementation

[0055] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0056] The average particle size of Fe3O4 NPs is 100-200 nm.

[0057] Preparation Example 1: Loaded Oxonium Salt Microspheres

[0058] The preparation method is as follows:

[0059] T1. Add 0.5g Fe3O4 NPs to 120mL ethanol, add 1g methyl orthosilicate, stir and mix evenly, add 20mL water, 0.2g hexadecyltrimethylammonium bromide and 0.3g ammonia, stir and react for 12h, separate with a magnet, wash, dry, calcine at 450℃ for 3h to obtain mesoporous magnetic SiO2 microspheres;

[0060] T2. Add 1g of mesoporous magnetic SiO2 microspheres to 150mL of ethanol, add 3g of 3-chloropropyltrimethoxysilane and 1mL of ammonia, heat and reflux and stir for 3h, separate with a magnet, wash and dry to obtain chlorine-modified mesoporous magnetic SiO2 microspheres.

[0061] T3. Add 2.5g of chlorine-modified mesoporous magnetic SiO2 microspheres and 1g of N-methylimidazole to 150mL of chloroform, heat and reflux for 20h under nitrogen protection, separate by magnet, wash and dry to obtain quaternary ammonium chloride-modified magnetic microspheres.

[0062] T4. Add 5g of quaternary ammonium chloride-modified magnetic microspheres to 200mL of ethanol, add 2.5g of sodium tetrafluoroborate, and simultaneously add 0.5g of D201 anion exchange resin. Stir the reaction at room temperature for 12h, separate with a magnet, wash, and test the final wash solution to ensure it does not contain Cl. - (If no white AgCl precipitate forms after adding 0.1 mol / L AgNO3 solution, it indicates that Cl...) - (After being completely washed), modified mesoporous magnetic SiO2 microspheres were obtained;

[0063] T5. Mix 1.5g of trimethyloxonium tetrafluoroboric acid and 5g of modified mesoporous magnetic SiO2 microspheres and add them to 50mL of dichloromethane. Stir the mixture at room temperature for 1h, and evaporate the solvent to obtain oxonium salt-loaded microspheres. Figure 1 The image shows the SEM image of the prepared oxonium salt microspheres. As can be seen from the image, the particle size of the microspheres is 200-500 nm.

[0064] Preparation Example 2: Loaded Oxonium Salt Microspheres

[0065] The preparation method is as follows:

[0066] T1. Add 1g Fe3O4 NPs to 120mL ethanol, add 1.2g tetraethyl orthosilicate, stir and mix evenly, add 20mL water, 0.3g hexadecyltrimethylammonium chloride and 0.5g ammonia water, stir and react for 15h, separate with a magnet, wash, dry, calcine at 550℃ for 1h to obtain mesoporous magnetic SiO2 microspheres.

[0067] T2. Add 3g of mesoporous magnetic SiO2 microspheres to 150mL of ethanol, add 5g of 3-chloropropyltrimethoxysilane and 1mL of ammonia, heat and reflux and stir for 5h, separate with a magnet, wash and dry to obtain chlorine-modified mesoporous magnetic SiO2 microspheres.

[0068] T3. Add 5g of chlorine-modified mesoporous magnetic SiO2 microspheres and 2g of N-methylimidazole to 150mL of chloroform, heat and reflux for 28h under nitrogen protection, separate by magnet, wash and dry to obtain quaternary ammonium chloride-modified magnetic microspheres.

[0069] T4. Add 5g of quaternary ammonium chloride-modified magnetic microspheres to 200mL of ethanol, add 5g of potassium tetrafluoroborate, and simultaneously add 1g of D201 anion exchange resin. Stir the mixture at room temperature for 24h, separate the microspheres using magnets, wash the mixture, and check the final washing solution for the presence of Cl. - (If no white AgCl precipitate forms after adding 0.1 mol / L AgNO3 solution, it indicates that Cl...) - (After being completely washed), modified mesoporous magnetic SiO2 microspheres were obtained;

[0070] T5. Mix 2g of trimethyloxonium tetrafluoroboric acid and 5g of modified mesoporous magnetic SiO2 microspheres and add them to 50mL of dichloromethane. Stir the mixture at room temperature for 2h, and evaporate the solvent to obtain oxonium salt-loaded microspheres.

[0071] Preparation Example 3: Loaded Oxonium Salt Microspheres

[0072] The preparation method is as follows:

[0073] T1. Add 0.7g Fe3O4 NPs to 120mL ethanol, add 1.1g tetraethyl orthosilicate, stir and mix evenly, add 20mL water, 0.25g hexadecyltrimethylammonium bromide and 0.4g ammonia, stir and react for 13h, separate with a magnet, wash, dry, calcine at 500℃ for 2h to obtain mesoporous magnetic SiO2 microspheres;

[0074] T2. Add 2g of mesoporous magnetic SiO2 microspheres to 150mL of ethanol, add 4g of 3-chloropropyltrimethoxysilane and 1mL of ammonia, heat and reflux and stir for 4h, separate with a magnet, wash and dry to obtain chlorine-modified mesoporous magnetic SiO2 microspheres.

[0075] T3. Add 3g of chlorine-modified mesoporous magnetic SiO2 microspheres and 1.5g of N-methylimidazole to 150mL of chloroform, heat under nitrogen protection and reflux for 24h, separate with a magnet, wash and dry to obtain quaternary ammonium chloride-modified magnetic microspheres.

[0076] T4. Add 5g of quaternary ammonium chloride-modified magnetic microspheres to 200mL of ethanol, add 3g of sodium tetrafluoroborate, and simultaneously add 0.7g of D201 anion exchange resin. Stir the reaction at room temperature for 18h, separate with a magnet, wash, and test the final wash solution to ensure it does not contain Cl. - (If no white AgCl precipitate forms after adding 0.1 mol / L AgNO3 solution, it indicates that Cl...) - (After being completely washed), modified mesoporous magnetic SiO2 microspheres were obtained;

[0077] T5. 1.7 g of trimethyloxonium tetrafluoroboric acid and 5 g of modified mesoporous magnetic SiO2 microspheres were mixed and added to 50 mL of dichloromethane. The mixture was stirred at room temperature for 1.5 h, and the solvent was evaporated to obtain oxonium salt-loaded microspheres.

[0078] Example 1 Synthesis of (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol

[0079] Synthesis route:

[0080] ;

[0081] Synthesis method:

[0082] S1. At room temperature, L-lactic acid (50 g, 0.56 mol) was dissolved in N,N-dimethylformamide (400 mL). Under nitrogen protection, imidazole (49.5 g, 0.73 mol) was added and stirred until dissolved. The reaction solution was cooled, and the reaction temperature was controlled at 0-10 °C. Tert-butyldimethylchlorosilane (88.8 g, 0.59 mol) was slowly added. After the addition was complete, the temperature was raised to 20-25 °C, and the reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was completed, the reaction solution was slowly poured into water. After complete quenching, ethyl acetate (500 mL) was added and stirred. The mixture was separated into layers. The organic phase was washed with saturated sodium chloride solution (500 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was distilled under reduced pressure to obtain an oily substance (2R)-2-{[dimethyl(2-methylpropyl-2-yl)silyl]oxy}propionamide (105.5 g, yield 90.9%).

[0083] S2. At room temperature, (2R)-2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}propionamide (50 g, 0.24 mol) was dissolved in dichloromethane (500 mL). Under nitrogen protection, the reaction temperature was controlled at 20-25 °C. Trimethyloxonium tetrafluoroborate (54.5 g, 0.36 mol) was added and stirred overnight. The reaction was monitored by phosphomolybdic acid on a silica gel plate. After the reaction was completed, pyridine (116.7 g, 1.45 mol) and methoxyamine hydrochloride (102.7 g, 1.21 mol) were added dropwise at 0-10 °C. After the addition was completed, the reaction was controlled at 0-10 °C and monitored by LCMS. After the reaction was completed, the reaction solution was added dropwise to 500 mL of 1 mol / L hydrochloric acid aqueous solution and stirred. The layers were separated, and the organic phase was washed successively with 500 mL of 1 mol / L hydrochloric acid aqueous solution, 500 mL of saturated sodium bicarbonate, and 500 mL of water. The phase was dried, filtered, concentrated, and separated by rapid column chromatography (PE:EA=30:1). The phase was concentrated to obtain an oily substance (2R)-2-{[dimethyl(2-methylpropyl-2-yl)silyl]oxy}-1-[(E)-methoxynimidyl]propyl-1-amine (44.3 g, yield 76.8%).

[0084] S3. At room temperature, (2R)-2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-[(E)-methoxyazine]prop-1-amine (10 g, 41.9 mmol) was added dropwise to a hydrochloric acid-methanol solution (60 mL, 4 mol / L). After the addition was complete, the reaction was carried out at 20-25 °C, and the reaction was monitored by LCMS. After the reaction was completed, the reaction solution was concentrated, methanol (100 mL) and sodium carbonate (10 g) were added to release the free solution, the mixture was filtered, concentrated, dissolved in dichloromethane (100 mL), filtered, concentrated, and the crude product was slurried in petroleum ether (100 mL), filtered, and dried to obtain a white solid (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol (4.0 g, yield 80.7%). Figure 2 The 1H NMR spectrum of (2R)-1-amino-1-[(E)-methoxynimidyl]prop-2-ol (solvent: DMSO) shows that the compound was successfully synthesized.

[0085] The overall yield of the product was 56.3%.

[0086] Example 2 Synthesis of (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol

[0087] Synthesis route:

[0088] ;

[0089] Synthesis method:

[0090] S1. At room temperature, L-lactic acid (100 g, 1.12 mol) was dissolved in DMF (400 mL). Under nitrogen protection, imidazole (99 g, 1.46 mol) was added and stirred until dissolved. The reaction solution was cooled, and the reaction temperature was controlled at 0-10℃. Triisopropylchlorosilane (227 g, 1.18 mol) was slowly added. After the addition was complete, the temperature was raised to 20-25℃. The reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was completed, the reaction solution was slowly poured into water. After complete quenching, ethyl acetate (500 mL) was added and stirred. The mixture was separated into layers. The organic phase was washed with saturated sodium chloride solution (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily substance (2R)-2-{[tris(prop-2-yl)methoxy]oxy}propionamide (303.0 g, yield 90.4%).

[0091] S2. At room temperature, (2R)-2-{[tris(prop-2-yl)silyl]oxy}propionamide (250 g, 0.93 mol) was dissolved in dichloromethane (2.5 L). Under nitrogen protection, the reaction temperature was controlled at 20-25 °C. Trimethyloxonium tetrafluoroborate (225 g, 1.4 mol) was added and stirred overnight. The reaction was monitored by phosphomolybdic acid on silica gel plates. After the reaction was completed, pyridine (450 g, 5.57 mol) was added dropwise at 0-10 °C. Methoxyamine hydrochloride (400 g, 4.64 mol) was added. After the addition was completed, the reaction was controlled at 0-10 °C and monitored by LCMS. After the reaction was completed, the reaction solution was added dropwise to a 1 mol / L hydrochloric acid aqueous solution and stirred. The layers were separated, and the organic phase was washed successively with a 1 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate, and water. The phase was dried, filtered, concentrated, and separated by rapid column chromatography (PE:EA=30:1). After concentration, an oily substance (2R)-1-[(E)-methoxynitriloides]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine (216.4 g, yield 77.5%) was obtained.

[0092] S3. At room temperature, (2R)-1-[(E)-methoxyazine]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine (100 g, 0.35 mol) was dissolved in tetrahydrofuran (500 mL). Stirring was started, and the reaction temperature was controlled at 20-25 °C. Tetrabutylammonium fluoride (350 mL, 0.35 mol, 1 mol / L tetrahydrofuran solution) was added. After the addition was complete, the reaction was continued at 20-25 °C, and the reaction was monitored using a silica gel plate with potassium permanganate for color development. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (PE:EA = 20:1-2:1). The solution was then concentrated to obtain a white solid (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol (24.5 g, yield 59.3%).

[0093] The overall yield of the product was 41.5%.

[0094] Example 3

[0095] Compared with Example 2, the only difference is that 225g of trimethyloxonium tetrafluoroboric acid was replaced by 650g of the oxonium salt microspheres prepared in Preparation Example 1, and the yield of (2R)-1-[(E)-methoxynimidyl]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine in step S2 was 84.5%.

[0096] Specifically, at room temperature, (2R)-2-{[tris(prop-2-yl)methoxy]oxy}propionamide (250 g, 0.93 mol) was dissolved in dichloromethane (2.5 L). Under nitrogen protection, the reaction temperature was controlled at 20-25 °C. 650 g of oxyonium salt microspheres were added and stirred overnight. The reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was completed, the microspheres were separated by a magnet. Pyridine (450 g, 5.57 mol) was added dropwise at a controlled temperature of 0-10 °C. Methoxyamine hydrochloride (400 g, 4.64 mol) was then added. After the addition was complete, the reaction was maintained at 0-10 °C, and the reaction was monitored by LCMS. After the reaction was completed, the reaction solution was added dropwise to a 1 mol / L hydrochloric acid aqueous solution and stirred. The layers were separated, and the organic phase was washed successively with a 1 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate, and water. The phase was dried, filtered, concentrated, and separated by rapid column chromatography (PE:EA=30:1). After concentration, an oily substance (2R)-1-[(E)-methoxynitriloides]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine (235.9 g, yield 84.5%) was obtained.

[0097] Example 4

[0098] Compared with Example 3, the only difference is that 650g of the oxyonium salt microspheres prepared in Preparation Example 1 were replaced by 530g of the oxyonium salt microspheres prepared in Preparation Example 2, and the yield of (2R)-1-[(E)-methoxynimidyl]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine in step S2 was 86.2%.

[0099] Example 5

[0100] Compared with Example 3, the only difference is that 650g of the oxyonium salt microspheres prepared in Preparation Example 1 were replaced by 590g of the oxyonium salt microspheres prepared in Preparation Example 3, and the yield of (2R)-1-[(E)-methoxynimidyl]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine in step S2 was 85.9%.

[0101] Example 6

[0102] The microspheres obtained after the reaction in Example 3 were reacted again according to step T5 of Preparation Example 1 to obtain oxyonium salt-loaded microspheres 2. These oxyonium salt-loaded microspheres 2 were then involved in step S2 of Example 4, with the reaction operation being the same as in Example 4. In this reaction, the yield of (2R)-1-[(E)-methoxyazine]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine in step S2 was 81.8%. This demonstrates that the microspheres after the reaction can be reused multiple times while still maintaining a good reaction yield.

[0103] Example 7 Synthesis of (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol

[0104] Synthesis route:

[0105] ;

[0106] Synthesis method:

[0107] S1. Turn on nitrogen protection. At 15-25℃, add N,N-dimethylformamide (1134g) to the reactor and start stirring. Then add L-lactic acid (300g) and imidazole (297g). Cool down to 0-10℃ and add triisopropylchlorosilane (681g) dropwise to the reaction system. After the addition is complete, stir at 20-30℃ for 2-3 hours. Monitor the reaction of the raw materials by TLC until they are completely reacted. Add water (3000g) to the reaction solution to quench the reaction under the control of 25℃. Add ethyl acetate (2700g) for extraction. The aqueous phase label is to be discarded. The organic phase is extracted using saturated sodium chloride aqueous solution (3000g). The organic phase is filtered into a funnel lined with anhydrous sodium sulfate and rinsed once with ethyl acetate (300g). Concentrate the filtrate at 40-50℃ until no fraction flows out, then add dichloromethane (795g). Stir and mix thoroughly, then continue vacuuming and heating to concentrate once more. Cool to 15-25℃, break the vacuum, add dichloromethane (795g), stir until dissolved, and then pack into a container. Rinse the reaction vessel with dichloromethane (396g) before packing into a container for the next step. qNMR: 90.7%, yield 90.4%. The gas chromatogram of the product is shown below. Figure 3 As shown in the figure, the retention time of the raw material is 7.062 min and the peak area is negligible. The retention time of the product is 11.45 min and the peak area is 90.10%. The retention time of triisopropylsilanol is 7.582 min and the peak area is 1.18%.

[0108] S2. Under nitrogen protection, add a dichloromethane solution of the above product to the reactor at 15-25℃ and start stirring. Add dichloromethane (2650g), then add trimethyloxonium tetrafluoroboric acid (225g). Maintain the temperature at 15-25℃ and stir for 16 hours. Monitor the reaction of the raw materials by TLC until complete. Cool down to 0-10℃ and add pyridine (450g) dropwise to the reaction system at 0-10℃. After the addition is complete, maintain the temperature at 0-10℃ and stir for 0.5 hours. Continue to add methoxyamine hydrochloride (400g) and maintain the temperature at 0-10℃ and stir for 1 hour. Monitor the reaction of the raw materials by gas chromatography until complete. Maintain the temperature at 0-10℃ and add 1mol / L hydrochloric acid (2250g) to wash twice. Separate the liquid and liquid phases. Wash the organic phase with saturated sodium bicarbonate solution (2250g). First, the organic phase was separated and washed once with water (2250g). The organic phase was filtered through a funnel lined with sodium sulfate and rinsed once with dichloromethane (225g). The filtrate was concentrated at 40-50℃ until no more distillate flowed out. The filtrate was then filtered through a funnel lined with silica gel. The eluent was petroleum ether:ethyl acetate = 30:1. TLC analysis showed no product spot. The filtrate was concentrated at 40-50℃ until no more distillate flowed out. Tetrahydrofuran (225g) was added and stirred until homogeneous. Vacuum was then applied and the mixture was concentrated again by heating. The temperature was lowered to 15-25℃, the vacuum was broken, and tetrahydrofuran (225g) was added and stirred until dissolved. The mixture was then loaded into a container. The reactor was rinsed with tetrahydrofuran (225g) before being loaded into the container for the next step. GC quantitative analysis showed a purity of 90.6% and a yield of 74.5%. Figure 4 The figure shows the central control gas chromatogram. As can be seen from the figure, the retention time of the raw material is 11.45 min and the peak area is negligible. The retention time of the intermediate raw material in the first stage is 10.09 min and the peak area is 22.17%. Figure 5 The image shows the gas chromatogram of the product. The product has a retention time of 11.125 min and a peak area of ​​92.95%. The product with a retention time of 6.4 min is a derivative impurity of triisopropylsilanol.

[0109] S3. Under nitrogen protection, add the tetrahydrofuran solution of the above product to the reactor at 15-25℃ and start stirring. Add tetrahydrofuran (180g), then add 1mol / L tetrabutylammonium fluoride (163g) dropwise. After the addition is complete, maintain the temperature at 15-25℃ and stir for 2-3 hours. Monitor the reaction of the raw materials by TLC until the reaction is complete. Concentrate the reaction solution at 40-50℃ until no distillate flows out. Analyze the solution using an alumina column with petroleum ether:ethyl acetate = 30:1 as the eluent to remove small polar impurities (using phosphomolybdic acid for color development). Adjust the... The eluent was petroleum ether:ethyl acetate = 2:1. The product was eluted (ninhydrin colorimetric reaction). The reaction solution was concentrated at 40-50℃. After no more distillate flowed out, 100g of petroleum ether was added and stirred until homogeneous. The mixture was then further concentrated under vacuum and heated until no more distillate flowed out. The vacuum was then broken, and 300g of petroleum ether was added at 15-25℃ and stirred for 0.5h. The mixture was then filtered and washed once with 100g of petroleum ether. The filter cake was dried in an oven at 45℃ to constant weight to obtain 21g of white solid product, with a yield of 54.7%. Figure 6 The image shows the gas chromatogram of the product, with a retention time of 6.817 min and a peak area of ​​99.97%.

[0110] The overall product yield was 36.8%, and the reaction was a pilot-scale reaction.

[0111] Comparative Example 1: Synthesis of (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol

[0112] Synthesis route:

[0113] ;

[0114] S1. At room temperature, (2R)-2-hydroxypropionamide (100 g, 1.12 mol) was dissolved in DMF (400 mL). Under inert gas protection, imidazole (99 g, 1.46 mol) was added. After stirring until dissolved, the reaction solution was cooled, and the reaction temperature was controlled at 0-10℃. TIPSCl (227 g, 1.18 mol) was slowly added. After the addition was complete, the temperature was raised to 20-25℃, and the reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was completed, the reaction solution was slowly poured into water. After complete quenching, ethyl acetate (500 mL) was added and stirred. The mixture was separated into layers. The organic phase was washed with saturated sodium chloride solution (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily substance (2R)-2-{[tris(prop-2-yl)methoxy]oxy}propionamide (303.0 g, yield 90.4%, purity 92.5%).

[0115] S2. At room temperature, (2R)-2-{[tris(prop-2-yl)methsilyl]oxy}propionamide (200.0 g, 0.707 mol) was dissolved in toluene (2000 mL). While stirring, diatomaceous earth (200.0 g, 100% wt) and phosphorus pentasulfide (62.9 g, 0.293 mol) were added. After the addition was complete, the reaction was carried out at 20-25 °C, and the reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with toluene, the filtrates were combined, and the mixture was washed with 10% sodium chloride solution (1000 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily substance (2R)-1-amino-2-{[tris(prop-2-yl)methsilyl]oxy}prop-1-thione (214.3 g, yield 49.8%).

[0116] S3. At room temperature, (2R)-1-amino-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-thione (190.0 g, 0.312 mol) was dissolved in pyridine (1900 mL), the mixture was stirred and heated, and the reaction temperature was controlled at 65-75 °C. Methoxyamine hydrochloride (130.5 g, 1.56 mol) was added. After the addition was complete, the reaction was controlled at 65-75 °C. The reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrates were combined and concentrated, ethyl acetate (1000 mL) was added and stirred to dilute, 10% sodium chloride solution (1000 mL × 2) was added to wash, anhydrous sodium sulfate was dried, filtered and concentrated to obtain crude product, which was purified by column chromatography (PE:EA = 30:1) to obtain oily substance (2R)-1-[(E)-methoxyazine]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine (40.9 g, yield 47.7%).

[0117] S4. At room temperature, (2R)-1-[(E)-methoxyazine]-2-{[tris(prop-2-yl)methoxy]oxy}prop-1-amine (0.15 g, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL). Stirring was started, and the reaction temperature was controlled at 20-25 °C. Tetrabutylammonium fluoride (0.54 mL, 0.5 mmol, 1 mol / L tetrahydrofuran solution) was added. After the addition was complete, the reaction was continued at 20-25 °C, and the reaction was monitored using a silica gel plate with potassium permanganate for color development. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (PE:EA = 20:1-2:1). The solution was then concentrated to obtain a white solid (2R)-1-amino-1-[(E)-methoxyazine]prop-2-ol (28 mg, yield 43.4%).

[0118] The overall product yield was only 9.54%, and this reaction was a small-scale reaction, with a yield significantly lower than that of Examples 1-3.

[0119] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a chiral α-hydroxy-gammoxime ether, characterized in that, Includes the following steps: S1. By protecting the hydroxyl group of chiral α-hydroxypropionamide with a protecting group, a chiral α-protecting group-propionamide is prepared. The structural formula of the chiral α-hydroxypropionamide is as follows: The structural formula of the chiral α-protecting group-propionamide is as follows; ; S2. Chiral α-protecting propionamide was reacted sequentially with an oxonium salt donor and an alkoxyamine hydrochloride to prepare chiral 1-[(E)-alkoxynitro]-α-protecting propan-1-amine, with the following structural formula: ; S3. Deprotect the chiral 1-[(E)-alkoxynimidyl]-α-protecting group-propane-1-amine to obtain the product, the structural formula of which is shown in Formula I: ； Formula I.

2. The preparation method according to claim 1, characterized in that, R1 and R2 are each independently C1-C 12 alkyl chain.

3. The preparation method according to claim 2, characterized in that, Both R1 and R2 are CH3.

4. The preparation method according to claim 1, characterized in that, The protecting group is a silane protecting group; the chiral α-hydroxypropionamide is L-lactamide; the alkoxyamine hydrochloride is methoxyamine hydrochloride; and the oxonium salt donor is trimethyloxonium tetrafluoroboric acid or oxonium salt-supported microspheres.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the chiral α-protecting group propionamide, trimethyloxonium tetrafluoroboric acid, and alkoxyamine hydrochloride is 1:(1.5-2):(5-6).

6. The preparation method according to claim 1, characterized in that, In step S2, the reaction with the oxonium salt donor is carried out under an inert gas atmosphere, at a temperature of 15-25°C, and for a time of 12-20 hours.

7. The preparation method according to claim 1, characterized in that, In step S2, the reaction with alkoxyamine hydrochloride is carried out under an inert atmosphere, with the addition of an acid-binding agent, a temperature of 0-10℃, and a reaction time of 1-2 hours.

8. The preparation method according to claim 7, characterized in that, The acid-binding agent is pyridine or triethylamine.

9. The preparation method according to claim 4, characterized in that, The protecting group is triisopropylsilyl, and the reagent used to remove the protecting group in step S3 is tetrabutylammonium fluoride.

10. The preparation method according to claim 4, characterized in that, The protecting group is tert-butyldimethylsilyl, and the reagent used to remove the protecting group in step S3 is hydrochloric acid.

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