Synthetic methods of N-alkoxycarbonyl-4-amino-4-alkylpiperidine

Abstract

This invention belongs to the field of heterocyclic pharmaceutical intermediate synthesis technology, specifically disclosing a method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine. Using N-alkoxycarbonylpiperidine-4-carboxylate as the starting material, the target product is obtained through a four-step reaction involving alkylation, hydrolysis, amidation, and Hoffmann rearrangement. This invention, through the adaptation and control of the substrate, synthetic route, and synthetic conditions, can solve the problems existing in the substrate-based synthetic route, thereby improving product yield and quality. The method described in this invention achieves a total yield of ≥60% of the target product, with key impurities all <0.1%. The process is safe and controllable, suitable for both laboratory-scale and industrial-scale production.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic pharmaceutical intermediate synthesis technology, specifically relating to the synthesis of pharmaceutical intermediates of N-alkoxycarbonyl-4-amino-4-alkylpiperidine. Background Technology

[0002] N-alkoxycarbonyl-4-amino-4-alkylpiperidines, such as the common N-Boc-4-amino-4-methylpiperidine, are important nitrogen-containing heterocyclic pharmaceutical organic compounds. Their molecular structures contain a piperidine ring, an ester protecting group, and amino groups, making them core building blocks in drug molecule design and synthesis. These compounds can be used to synthesize central nervous system drugs such as antidepressants, antipsychotics, and analgesics. They can also serve as key intermediates for kinase inhibitors in the development of antitumor drugs, and have potential applications in organic synthesis and functional materials.

[0003] For example, existing methods for synthesizing N-Boc-4-amino-4-methylpiperidine mainly fall into two categories:

[0004] The first method is the hydroxyl → azide → reduction method, which uses N-Boc-4-hydroxy-4-methylpiperidine as a raw material. The hydroxyl group is converted to an azide group via the Mitsunobu reaction, followed by catalytic hydrogenation to reduce it to an amino group. This two-step reaction yields N-Boc-4-amino-4-methylpiperidine. This method uses highly toxic sodium azide, and azides are prone to explosion upon heating or impact, posing significant safety hazards. Furthermore, the azide step easily generates byproducts, and incomplete azide reduction produces azo and triazole genotoxic impurities, making waste treatment difficult.

[0005] The second method is the cyano reduction method, which uses N-Boc-4-methyl-4-cyanopiperidine as a raw material and Raney nickel or Pd / C catalytic hydrogenation to directly reduce the cyano group to an amino group. This method is limited by the scarcity of commercially available N-Boc-4-methyl-4-cyanopiperidine, requiring in-house synthesis and increasing process complexity. Furthermore, it requires high-pressure hydrogenation at 3-5 atm (atm refers to standard atmospheric pressure), resulting in significant equipment investment and high costs. During the preparation process, Pd / C and Raney nickel catalysts introduce heavy metal residues such as Pd, Ni, and Cr. The Boc protecting group readily undergoes hydrogenolysis, generating free 4-amino-4-methylpiperidine impurities. These impurities differ from the target product structure by only one protecting group and have highly similar polarity, making them impossible to separate using conventional methods. They are critical impurities strictly controlled in pharmaceutical applications, and the content of these impurities in existing hydrogenation methods is generally >0.5%, even exceeding 1%.

[0006] In summary, existing methods for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidines, such as the common N-Boc-4-amino-4-methylpiperidine, still have shortcomings such as high cost, unsatisfactory substrate conversion rate, and difficulty in controlling process synthesis impurities. Summary of the Invention

[0007] To overcome the above-mentioned shortcomings, this invention provides a method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine, aiming to provide a novel synthetic route and process for N-alkoxycarbonyl-4-amino-4-alkylpiperidine.

[0008] As pharmaceutical intermediates, in addition to conventional organic synthesis indicators such as raw material conversion rate and product yield, another important indicator is the issue of process impurities. For pharmaceutical intermediates, impurities need to be clearly identified and controlled to facilitate the qualified production of drugs. However, in existing methods for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine, such reactions often require vigorous reaction mechanisms such as heavy metal catalysts, and the process impurities of the product are difficult to control, hindering industrial-scale production. To address this situation, this invention, through in-depth research, provides the following synthetic approach and further optimizes and adapts it to overcome the synthetic challenges it faces, as detailed below:

[0009] A method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine, comprising the following steps:

[0010] Step 1: The additives of Formula 1 and Formula 2 and alkyllithium are pre-reacted, followed by the dropwise addition of haloalkane R4X to carry out the alkylation reaction, and the product of Formula 3 is obtained.

[0011] Formula 1; Formula 2; Formula 3;

[0012] In Formula 1, R1~R2 are C1~C6 alkyl groups; in Formula 2, R3 is a C1~C6 alkyl group; in R4X, R4 is a C1~C6 alkyl group and X is a halogen.

[0013] Step 2:

[0014] The product of Formula 3 was hydrolyzed in an aqueous alcohol solution under the action of an alkali, and then acidified to obtain the product of Formula 4; wherein the volume ratio of alcohol to water in the aqueous alcohol solution was 1~1.2:1;

[0015] Equation 4;

[0016] Step 3:

[0017] Formulas 4, 5, 6, and 7 were pre-reacted, followed by amidation with ammonia to obtain product 8.

[0018] Formula 5; Formula 6; Formula 7;

[0019] In Formula 6, R5 is a C1-C4 alkyl group; in Formula 7, R6 is a C1-C4 alkyl group.

[0020] Formula 8;

[0021] Step 4:

[0022] Formula 8 was rearranged in the presence of a base and the assistance of Formula 9 to prepare N-alkoxycarbonyl-4-amino-4-alkylpiperidine of Formula 10.

[0023] Equation 9;

[0024] In Formula 9, R7 is a C1~C4 alkyl group;

[0025] Formula 10.

[0026] Based on the structural characteristics of N-alkoxycarbonyl-4-amino-4-alkylpiperidine, this invention provides a novel synthetic approach based on Formula 1, involving alkylation, selective hydrolysis, amidation, and rearrangement. The synthetic route is shown in Reaction Formula 1 below:

[0027]

[0028] Reaction 1.

[0029] This invention also demonstrates that implementing the novel synthetic route using Formula 1 as a substrate faces numerous challenges, primarily due to the high steric hindrance and easy deesterification protection of Formula 1. To address these challenges, this invention innovatively pre-alkylates Formula 1 with the assistance of Formula 2 and alkyllithium, followed by selective ester hydrolysis, amidation with the assistance of Formulas 5-7, and finally rearrangement with the assistance of Formula 9. This allows for the mild synthesis of the target product without precious metal catalysts, based on the synergistic combination of additives and conditions in the synthetic route. The method described in this invention features mild reaction conditions, requires no precious metal catalysts, achieves high conversion rates, and maintains stable and controllable process impurities. Studies show that the impurities in this method are stable and controllable, with no intermediate impurities such as hydrogen deprotection protection, piperidine ring opening, or incomplete reduction. The content of key impurities in the final product can be controlled below 0.05%. Furthermore, the synthetic process of this invention is simple, easy to implement, and eliminates the use of heavy metal catalysts, thus eliminating the risk of heavy metal residues and meeting the most stringent control standards of ICH Q3D.

[0030] This invention demonstrates that achieving the α-alkylation, selective hydrolysis, amidation, and rearrangement of the substrate of Formula 1 is challenging. The main difficulties lie in: 1. Insufficient reactivity: The reaction site of the substrate of Formula 1 is attached to the quaternary carbon of the piperidine ring, resulting in significant steric hindrance. Conventional alkylation processes cannot effectively activate the functional group, leading to reaction conversion rates generally below 65% and significant raw material residue. Furthermore, harsh reaction conditions easily cause deesterification and piperidine ring opening, generating uncontrollable unknown process impurities. 2. Instability of protecting group and ring structure: The 1-position ester protecting group of the substrate of Formula 1 is extremely sensitive to strong acids, strong bases, and high temperatures. Conventional alkylation, ester hydrolysis, and amidation processes easily lead to complete ester removal and piperidine ring opening, among other side reactions. 3. Uncontrollable pharmaceutical-grade impurities: Under strong reaction conditions, the quaternary carbon structure of the substrate of Formula 1 is prone to C-C bond breakage and elimination rearrangement, generating difficult-to-separate isomer impurities. General processes cannot control these impurities at the source, resulting in product purity below 95%, which fails to meet pharmacopoeia requirements for pharmaceutical intermediates. To address the problems existing in the implementation of the above-mentioned substrate of Formula 1 and synthetic approach, this invention innovatively combines and controls the conditions of alkylation, ester hydrolysis, amidation, and rearrangement in a suitable manner. This enables the successful implementation of the synthetic approach and the successful synthesis of pharmaceutical intermediates that meet pharmacopoeia requirements.

[0031] This invention demonstrates that, compared to ordinary chain esters and piperidine derivatives without quaternary carbon, the substrate of Formula 1 suffers from alkylation challenges such as large steric hindrance, easy ring-opening of the piperidine ring under alkaline conditions, and easy removal of protecting groups at R1 and R2. To address these challenges, this invention innovatively employs a pre-reaction with Formula 2 and alkyllithium assistance, followed by alkylation with a haloalkane. This approach leverages the unique characteristics of the Formula 1 substrate, enabling highly selective alkylation at the 4-position of the piperidine ring, improving conversion rates, controlling related impurities, and enhancing the quality stability of pharmaceutical intermediates.

[0032] In this invention, in step 1, the reaction solvent for alkylation includes at least one of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, and dimethyl ethylene glycol (DME);

[0033] Alkyl lithium is C1 to C6 alkyl lithium, and can further be n-butyl lithium.

[0034] In this invention, the molar ratio of the additives of Formula 1 and Formula 2 to alkyllithium is 1:2.1~2.5:1.8~2.2;

[0035] The molar ratio of Formula 1 and haloalkane R4X is 1:1.8~2.2.

[0036] In this invention, the temperature of the pre-reaction process is -20 to -40 °C; the temperature of adding haloalkanes R4X is -75 to -45 °C; after the addition of haloalkanes R4X is completed, the temperature is raised to 5 to 40 °C and the reaction is stirred.

[0037] In this invention, the progress of the reaction can be reasonably monitored using conventional central control methods, such as chromatographic methods.

[0038] This invention has discovered that innovatively optimizing the control of the reaction temperature helps to further synergize and adapt to the characteristics of substrate 1, solving the alkylation problems caused by its easy degreasing and large steric hindrance, further improving the alkylation product, effectively reducing related process impurities, and improving the quality of the product.

[0039] The pre-reaction time is 4-6 h, the dropwise addition time of haloalkane R4X is 1-3 h, and the stirring reaction time after the dropwise addition of haloalkane R4X is completed is 1-2 h.

[0040] Previous studies of this invention have also shown that direct ammonolysis of Formula 3 can also yield the product of Formula 8, and this synthetic route is shorter. However, it is difficult to adapt to the physicochemical characteristics of the substrate of this invention, making it difficult to obtain Formula 8 in high yield and hindering the stable control of related impurities. Therefore, this invention has conducted in-depth research showing that innovatively performing hydrolysis and ammonolysis of Formula 3, combined with the joint control of parameters such as solvent and alkali dosage during the hydrolysis process, and the joint control of ammonolysis conditions, can achieve highly selective hydrolysis and ammonolysis of the ester group at R1, which is beneficial to the overall conversion rate of the process and the stable control of related impurities.

[0041] In this invention, in step 2, the alcohol in the alcohol-water solution is a C1-C4 alcohol, and may further be methanol, ethanol, isopropanol, etc.

[0042] The volume ratio of alcohol to water in an alcohol-water solution can be adjusted as needed, for example, it can be 1~1.2:1;

[0043] The alkali is an alkali metal hydroxide, and may further be at least one of sodium hydroxide and potassium hydroxide;

[0044] The molar ratio of the product of Formula 3 to the base is 1:1.8~2.2;

[0045] The hydrolysis reaction is carried out at reflux.

[0046] In this invention, the acid used in the acidification process is an inorganic strong acid, such as hydrochloric acid, sulfuric acid, or other inorganic strong acids.

[0047] The pH at the end of acidification is 3-4.

[0048] In this invention, both the hydrolysis and acidification reactions can be controlled using conventional methods such as chromatography. For example, the reflux reaction time can be 2.5–3.5 h.

[0049] In this invention, in step 3, the solvent for the amidation reaction includes at least one of dichloromethane (DCM), 1,2-dichloroethane (DCE), and 2-MeTHF;

[0050] The molar ratios of Equations 4 and 5, and Equations 6 and 7 are 1:1.1~1.3:2.8~3.2:1.8~2.2;

[0051] The molar ratio of Formula 4 and ammonia is 1:1.8~2.2.

[0052] In this invention, in step 3, the pre-reaction temperature is 20~25 ℃ and the time is 2.5~3.5 h;

[0053] The temperature of ammonia water addition is controlled below 20 ℃, and the reaction is carried out at 20~25 ℃ after the addition is completed.

[0054] In this invention, in step 4, the solvent for the rearrangement reaction includes at least one of acetonitrile, acetone, THF, and 2-MeTHF;

[0055] The alkali is an alkali metal hydroxide, and may further be at least one of sodium hydroxide and potassium hydroxide;

[0056] The molar ratio of Formula 8, alkali and Formula 9 is 1:4.2~4.8:0.5~0.6.

[0057] In step 4 of this invention, the alkali is dissolved in water and cooled to 0-5 °C. Acetonitrile and Formula 8 are added and then cooled to -5-0 °C. Formula 9 is then added in batches while controlling the temperature of the addition process to be below 0 °C. After Formula 8 is added, the mixture is kept warm and stirred for 0.5-1 h, then heated to 40-50 °C and reacted for 10-14 h to obtain the N-alkoxycarbonyl-4-amino-4-alkylpiperidine of Formula 10.

[0058] Beneficial effects

[0059] (1) Outstanding technological innovation:

[0060] This invention is not a simple combination of existing conventional reactions, but rather an innovative four-step synthetic process designed for a specific substrate with a unique formula 1: "an alkoxycarbonyl sensitive protecting group at the N-position and a geminal disubstituted quaternary carbon at the 4-position". The entire four-step reaction process is customized and optimized, with each step's conditions closely tied to the substrate's specificity. This invention solves a series of technical pain points in existing general processes for this substrate, such as low reactivity, easy removal of the protecting group, easy ring-opening of the piperidine ring, numerous byproducts, and difficulty in controlling impurities. It has outstanding substantive features and significant progress.

[0061] (2) Precise control of impurities, suitable for pharmaceutical applications: This invention inhibits the generation of by-products from the source. Through customized condition control of each step, the content of five key pharmaceutical impurities, namely alkoxycarbonyl dehydrogenates, piperidine ring openers, N-oxides, quaternary carbon isomers, and unreacted amide intermediates, in the target product is all less than 0.1%. The impurity control limit for pharmaceutical industrial production can be directly used for subsequent innovative drug synthesis without additional purification, ensuring the safety and effectiveness of drug synthesis.

[0062] (3) The operation is safe and controllable, and the applicability is wide: low-toxicity and low-risk reagents are selected, and high-risk reagents such as highly toxic sodium azide and highly corrosive liquid bromine in the existing process are eliminated. The reaction conditions of each step are mild, without extreme high temperature and high pressure, and the operation is safe and controllable. The process is highly repeatable, and the yield and purity of different batches fluctuate by less than 2%, which is suitable for laboratory small-scale testing and industrial scale-up production.

[0063] (4) Low cost and significant industrial advantages: The amount of reagent used is optimized and reasonable, the solvent can be recycled and reused, and there is less waste; all post-processing steps adopt mature industrial processes such as crystallization, extraction, and pH switching, which do not require column chromatography purification, greatly reducing purification costs and improving production efficiency, making it suitable for large-scale industrial production from hundreds of kilograms to tons.

[0064] (5) Strong structural extensibility: Piperidine derivatives with different substitutions can be prepared by adjusting methylation and rearrangement conditions, which can meet the needs of more innovative drug research and development and have broad application prospects. Attached Figure Description

[0065] Figure 1 The 1H NMR spectrum of N-Boc-4-amino-4-methylpiperidine, the final synthesized in Example 1;

[0066] Figure 2 The image shows the liquid chromatography (HPLC) chromatogram of N-Boc-4-amino-4-methylpiperidine, which was finally synthesized in Example 1. Detailed Implementation

[0067] This invention provides a method for optionally producing N-Boc-4-amino-4-methylpiperidine, using methyl N-Boc-4-piperidinecarboxylate as a starting material, and obtaining the target product through four consecutive reactions: methylation, hydrolysis, amidation, and rearrangement. Detailed technical solutions for each step are as follows:

[0068] Step 1: Methylation reaction of N-Boc-piperidine-4-carboxylic acid ester:

[0069] Under nitrogen protection, formula 2A (R3 is methyl of formula 2) was mixed with tetrahydrofuran (THF), cooled to below -30 °C, and n-butyllithium solution was added dropwise. After stirring and maintaining the temperature, the mixture was cooled to below -50 °C, and a mixed solution of N-Boc-4-piperidinecarboxylate and THF was added dropwise. Iodomethane was then added dropwise. After the reaction was maintained and heated, the mixture was quenched with dilute hydrochloric acid, and the final product was N-Boc-4-methylpiperidine-4-carboxylate.

[0070] The feeding ratio of each material in step 1 is: methyl N-Boc-piperidine-4-carboxylate: Formula 2A: n-butyllithium: iodomethane = 1.0: 2.1~2.5: 1.8~2.2: 1.8~2.2; the total amount of THF is 7~8 times the volume of methyl N-Boc-piperidine-4-carboxylate, of which 7.5~7.8 times the volume of THF is used to dissolve Formula 2A, and the remaining THF is used to dissolve methyl N-Boc-piperidine-4-carboxylate.

[0071] The dropping temperature of n-butyllithium was controlled at -30 to -40 °C, and the dropping time was 4 to 5 h. After the dropping was completed, the mixture was kept at the temperature and stirred for 0.5 to 1 h. The dropping temperature of the mixed solution of N-Boc-piperidine-4-carboxylate and THF was controlled at -50 to -60 °C, and the dropping time was 1.5 to 2.5 h. After the dropping was completed, the mixture was kept at the temperature and stirred for 0.5 to 1 h. The dropping temperature of iodomethane was controlled below -50 °C. After the dropping was completed, the mixture was kept at the temperature and stirred for 0.5 to 1 h. Then, the mixture was transferred to an ice-water bath and heated to 10 to 20 °C. The reaction was carried out for 1 to 2 h.

[0072] This step employs a composite system composed of Formula 2A and n-butyllithium, along with a optimized gradient temperature control program, adapted to the quaternary carbon steric hindrance and Boc-sensitive protecting group characteristics of N-Boc-piperidin-4-carboxylate, thus solving the technical problems of low hydrogen removal efficiency and easy Boc removal in a single strong base system. This step achieves methylation selectivity >99% and byproduct (Boc removal products, ring-opening products) content <0.05%.

[0073] Step 2: Hydrolysis of N-Boc-4-methylpiperidine-4-carboxylate: N-Boc-4-methylpiperidine-4-carboxylate was dissolved in methanol, cooled, and sodium hydroxide aqueous solution was added dropwise. The mixture was heated to reflux and the reaction was continued. After treatment, N-Boc-4-methylpiperidine-4-carboxylic acid was obtained.

[0074] In step 2, the feed ratio of each material is: methyl N-Boc-4-methylpiperidin-4-carboxylate: sodium hydroxide: concentrated hydrochloric acid = 1.0: 1.8~2.2: 2.1~2.5; the amount of methanol used is 2~2.5 times the volume of methyl N-Boc-4-methylpiperidin-4-carboxylate. The volume ratio of methanol to water is 1~1.2:1. The pH of acidification can be 3~4.

[0075] The specific reaction conditions for step 2 are as follows: the temperature of the sodium hydroxide aqueous solution added should not exceed 40 ℃. After the addition is complete, the temperature is raised to 65~70 ℃ and refluxed for 2.5~3.5 h. After the reaction is completed, the temperature is lowered to below 40 ℃, concentrated at 50 ℃ to remove methanol, and then lowered to 15~20 ℃. Concentrated hydrochloric acid is added dropwise to adjust the pH to 3~4.

[0076] This step uses a methanol-water mixed solvent and stoichiometric sodium hydroxide, and involves a medium-low temperature reflux reaction to avoid Boc deprotection and quaternary carbon bond cleavage caused by excessive strong alkali and high temperature. This step achieves 100% hydrolysis conversion, 100% Boc protecting group retention, and no quaternary carbon bond cleavage byproducts.

[0077] Step 3: Amidation reaction of N-Boc-4-methylpiperidine-4-carboxylic acid: Under nitrogen protection, N-Boc-4-methylpiperidine-4-carboxylic acid was dissolved in DCM, cooled, and then Formula 5 and Formula 6A (R5 is methyl of Formula 6) were added sequentially, followed by Formula 7A (R6 is methyl of Formula 7) in batches. After reacting at room temperature, ammonia was added dropwise to continue the reaction, and the post-treatment yielded N-Boc-4-methylpiperidine-4-carboxamide.

[0078] The feeding ratio of each material in step 3 is: N-Boc-4-methylpiperidine-4-carboxylic acid: Formula 5: Formula 6A: Formula 7A: ammonia water = 1.0: 1.1~1.3: 2.8~3.2: 1.8~2.2: 1.8~2.2; the amount of DCM used is 5~6 times the volume of N-Boc-4-methylpiperidine-4-carboxylic acid; the ammonia water is 25% by mass.

[0079] The specific reaction conditions for step 3 are as follows: the addition temperature of formulas 5 and 6A is controlled at 20~25 ℃, the addition temperature of formula 7A in batches is controlled at 20~25 ℃, and the reaction is allowed to proceed at room temperature for 2.5~3.5 h after the addition is complete; the ammonia water is added at a temperature below 20 ℃, and the reaction is allowed to proceed at room temperature until the intermediate state is completely eliminated after the addition is complete.

[0080] This step employs a composite activation system of Formula 5 and Formula 7A, along with a weakly basic acid-binding agent of Formula 6A, to overcome the instability of single-activator intermediates and the removal of Boc by strong-basic acid-binding agents. This step achieves 100% amidation conversion and product purity >98.5%, eliminating the need for column chromatography for purification.

[0081] Step 4: Rearrangement reaction of N-Boc-4-methylpiperidine-4-carboxamide: Dissolve potassium hydroxide in water, cool down and add acetonitrile and N-Boc-4-methylpiperidine-4-carboxamide, mix well and cool down to below 0 °C, add formula 9A in batches (R7 is methyl formula 9), keep warm and stir, then heat up to react, and post-process to obtain the target product N-Boc-4-amino-4-methylpiperidine;

[0082] The feeding ratio of each material in step 4 is: N-Boc-4-methylpiperidine-4-carboxamide: potassium hydroxide: formula 9A = 1.0: 4.2~4.8: 0.5~0.6; the amount of acetonitrile and water used is 2~2.5 times the volume of N-Boc-4-methylpiperidine-4-carboxamide.

[0083] The specific reaction conditions for step 4 are as follows: after dissolving potassium hydroxide in water, the temperature is lowered to 0~5 ℃, acetonitrile and N-Boc-4-methylpiperidine-4-carboxamide are added, and the temperature is lowered to -5~0 ℃. Formula 9A is added in batches with the temperature controlled below 0 ℃. After Formula 9A is added, the mixture is kept warm and stirred for 0.5~1 h, and then the temperature is raised to 40~50 ℃ and the reaction is carried out for 10~14 h.

[0084] This step uses Formula 9A selective oxidant instead of liquid bromine, employing a gradient temperature-controlled reaction to avoid piperidine epoxidation, Boc removal, and isomer formation. This step achieves 100% rearrangement conversion, with no N-oxides or isomer impurities, and the product purity meets pharmaceutical-grade requirements.

[0085] Example 1

[0086] A method for preparing N-Boc-4-amino-4-methylpiperidine, the specific steps of which are as follows:

[0087] Step 1: Methylation reaction of N-Boc-4-piperidinecarboxylate: In a 20 L three-necked flask, add 7.5 L of THF and Formula 2A (2.2 eq.), and purge with nitrogen three times after the addition is complete; under nitrogen protection, cool to below -30 °C using a dry ice-acetone system, and slowly add n-butyllithium (2.0 eq.) dropwise, controlling the temperature at -30 to -40 °C for 5 h; after the addition is complete, keep warm and stir for 0.5 h; continue cooling to below -50 °C, and add dropwise a mixed solution of 3 L of THF and 1500 g of N-Boc-piperidine-4-carboxylate (1 eq.), controlling the temperature at -50 to -60 °C for 2 h; after the addition is complete, keep warm and stir for 0.5 h; maintain the temperature at -50 °C. Below ℃, add 2.0 (eq.) iodomethane dropwise, controlling the dropping rate. After the addition is complete, keep the mixture warm and stir for 0.5 h. Transfer the reaction flask to an ice-water bath and slowly heat it to 10~20 ℃. React for 1.5 h until the starting material is completely converted.

[0088] Prepare 10 L of 1 mol / L dilute hydrochloric acid, control the temperature at 20 ℃, pour the reaction solution into acid water to quench it, and measure the pH to be 7~8; after thorough stirring, let it stand to separate the layers and separate the organic phase; extract the aqueous phase twice with ethyl acetate (EA), each time using 2.5 L, combine the organic phases, wash once with 2.5 L of saturated brine, concentrate to dryness, and obtain a brown oily substance, N-Boc-4-methylpiperidine-4-carboxylate;

[0089] HPLC showed that the product purity was 99.6%, Boc removal impurities were <0.05%, piperidine ring-opening impurities were <0.05%, and there were no other byproducts.

[0090] Step 2: Hydrolysis of N-Boc-4-methylpiperidin-4-carboxylate: In a 50 L reactor, add 1.0 eq. of N-Boc-4-methylpiperidin-4-carboxylate and 3.0 L of methanol, stirring until dissolved at room temperature; turn on the refrigeration and cool to 20°C; prepare a sodium hydroxide aqueous solution (2.0 equivalents, with a volume ratio of methanol to water in the sodium hydroxide aqueous solution of 1:1), and slowly add it dropwise to the reaction system, controlling the temperature not to exceed 40°C; after the addition is complete, raise the temperature to 65~70°C and reflux for 3 hours; after the raw materials are completely converted, cool to below 40°C, then add 2.3 (eq.) of concentrated hydrochloric acid, controlling the pH at the reaction endpoint to 3.5; concentrate at 50°C to remove methanol, cool to 15°C, and slowly add 1.2 L of concentrated hydrochloric acid; when the system becomes viscous, add 1 L of water to adjust the pH to 3~4; stir for 0.5 hours. h, filter, wash the filter cake twice with water, dry it with forced air at 60 ℃ to obtain white solid N-Boc-4-methylpiperidine-4-carboxylic acid;

[0091] HPLC purity 99.3%, Boc removal impurities <0.05%, quaternary carbon bond cleavage impurities <0.05%.

[0092] Step 3: Amidation reaction of N-Boc-4-methylpiperidine-4-carboxylic acid. In a 20 L reaction flask, 1-Boc-4-methylpiperidine-4-carboxylic acid (1.0 eq.) and 7.0 L DCM were added. The mixture was stirred at room temperature and purged twice with nitrogen. The temperature was lowered to 20 °C, and Formula 5 (1.2 eq.) and Formula 6A (3.0 eq.) were added sequentially, stirring until dissolved. The temperature was maintained at 20–25 °C, and Formula 7A (2.0 eq.) was added in portions, with slight exothermic reaction. After the addition was complete, the mixture was reacted at room temperature for 3 h. A sample was taken, and TLC analysis showed that the starting material was completely converted to the intermediate state. The temperature was lowered to below 20 °C, and 25% ammonia water (2.0 eq.) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature until the intermediate state completely disappeared. 5 L of saturated sodium carbonate solution was added, stirred, and allowed to stand for separation. 1.5 L of water and 3.5 L of DCM were added to the aqueous phase and the emulsion layer, and the mixture was stirred for 0.5 h. h, allow to stand and separate into layers, repeat extraction 3 times until the emulsion layer is completely dissolved; combine all DCM phases, wash once with 3 L saturated sodium carbonate solution, then wash twice with 1 mol / L hydrochloric acid, 3 L each time, to remove excess N-methylmorpholine (NMM); wash once with 3 L saturated sodium bicarbonate solution, then wash once with 3 L saturated brine solution, and dry with anhydrous sodium sulfate; concentrate most of the DCM to a remaining solvent of 2.8 L, add n-heptane (PE) twice, 3 L each time, to remove residual DCM, concentrate to a small volume, cool to crystallize; filter, rinse the filter cake with PE, and dry at 50 °C to obtain a pale yellow solid N-Boc-4-methylpiperidine-4-carboxamide;

[0093] HPLC purity 99.2%, Boc removal impurities <0.05%, acylurea byproducts <0.1%.

[0094] Step 4: Rearrangement reaction of N-Boc-4-methylpiperidine-4-carboxamide: In a 50 L reactor, add 2.5 L of water, cool to 0 °C, add 4.5 (eq.) potassium hydroxide, stir to dissolve, and cool to 0-5 °C; add 2.5 L acetonitrile and N-Boc-4-methylpiperidine-4-carboxamide (1.0 eq.), stir to mix, and cool to -5-0 °C; add Formula 9A (0.5 eq.) in portions, controlling the temperature below 0 °C; after the addition is complete, stir at low temperature for 0.5 h, raise the temperature to 40-50 °C, and react for 12 h; take a sample, and detect by TLC, the starting material is completely converted; cool to room temperature, allow to stand and separate the layers, and separate the organic phase; extract the aqueous phase 3-4 times with DCM, each time using 1.5 L, until no product residue remains in the aqueous phase; combine the organic phases, and add 6 L of 1... Adjust the pH to 3-4 with mol / L dilute hydrochloric acid, separate the phases, wash the aqueous phase twice with DCM, 1.5 L each time; adjust the pH of the aqueous phase to 10-11 with sodium hydroxide solution, then extract with DCM four times, 1.5 L each time; combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate until no droplets remain, and pump dry for 2 h to obtain a pale yellow oil N-Boc-4-amino-4-methylpiperidine;

[0095] The proton NMR spectrum of the product is shown below. Figure 1 The spectrum was analyzed to be N-Boc-4-amino-4-methylpiperidine.

[0096] HPLC chromatogram (column conditions: C18 (5 μm × 4.6 mm × 250 mm), mobile phase: methanol-water-triethylamine = 60:40:0.1, flow rate: 1 mL / min, wavelength: 210 nm, column temperature 30 ℃, run time 30 min) is shown below. Figure 2 The peak areas of the synthesized N-Boc-4-amino-4-methylpiperidine by HPLC are shown in Table 1:

[0097] Table 1: Peak Area of ​​HPLC

[0098] ;

[0099] The target product has a purity of 99.7%, and the contents of five key impurities—Boc removal product, piperidine ring-opening product, N-oxide, quaternary carbon isomer, and unreacted amide intermediate—are all below 0.1%, meeting the requirements for pharmaceutical intermediates.

[0100] The overall yield of this embodiment was 62.8% (based on methyl N-Boc-piperidine-4-carboxylate), and the purity of the target product N-Boc-4-amino-4-methylpiperidine was 99.7%, which meets the requirements for pharmaceutical intermediates.

[0101] Example 2

[0102] A method for preparing N-Boc-4-amino-4-methylpiperidine, which differs from Example 1 in that:

[0103] In step 1, the amount of Formula 2A is 2.1 (eq.), the amount of n-butyllithium is 1.9 (eq.), the amount of iodomethane is 1.9 (eq.), and the total amount of THF is 10.8 L;

[0104] In step 3, the feed amount in formula 5 is 1.13 (eq.), the feed amount in formula 6A is 2.87 (eq.), and the feed amount in formula 7A is 1.88 (eq.).

[0105] In step 4, the amount of potassium hydroxide added is 4.27 (eq.), and the amount of Equation 9A added is 0.52 (eq.).

[0106] The remaining steps, operating conditions, and post-processing methods are the same as in Example 1.

[0107] In this embodiment, 982 g of N-Boc-4-amino-4-methylpiperidine was finally obtained, with a total yield of 65.5% and a purity of 99.6%, which meets the requirements for pharmaceutical intermediates.

[0108] Example 3

[0109] A method for preparing N-Boc-4-amino-4-methylpiperidine, which differs from Example 1 in that:

[0110] In step 1, after the iodomethane is added dropwise, the mixture is kept warm and stirred for 1 hour, then heated to 15-25 °C and reacted for 1 hour.

[0111] In step 4, the temperature is raised to 45~55 °C, and the reaction is carried out for 10 h;

[0112] The remaining steps, operating conditions, and post-processing methods are the same as in Example 1.

[0113] In this embodiment, 991 g of N-Boc-4-amino-4-methylpiperidine was finally obtained, with an overall yield of 66.1% and a purity of 99.7%. Both the yield and purity were slightly improved, making it suitable for industrial scale-up.

[0114] Comparative Example 1

[0115] Compared with Example 1, the only difference is that Formula 2A is not added in step 1, while other operations and parameters are the same as in Example 1.

[0116] The preparation results of step 1 are as follows: the methylation conversion rate of formula 1 is only 64.3%, and the remaining by-product impurities are 35.6%, which are highly similar in polarity to the methylated formula 3. They are difficult to remove through post-processing. If they are continued to be put into the subsequent process, the impurities react with the base to generate more impurities. The final product yield is 39.2% and the purity is 79.2%. The product yield and purity are seriously reduced and have no practical industrial application value.

[0117] Comparative Example 2

[0118] Compared with Example 1, the only difference is that in step 2, the amount of water introduced into the sodium hydroxide aqueous solution is changed, and the alcohol-water ratio in the reaction system is controlled to be 0.6:1. The total volume of alcohol and water and other operations and parameters are the same as in Example 1.

[0119] The results showed that the hydrolysis conversion rate was only 72.1%, and the single-step by-product was 18.9%. The post-processing was difficult to remove similar impurities, which were then fed into subsequent processes, triggering a chain reaction. The final product yield was 16.4%, and the purity was 35.4%. The product yield and purity were severely reduced, and there was no practical industrial application value.

[0120] Comparative Example 3

[0121] Compared to Example 1, the only difference is that in step 3, triethylamine (TEA) is used instead of form 6A. All other operations and parameters are the same as in Example 1.

[0122] The conversion rate of 1-Boc-4-methylpiperidine-4-carboxamide was 71.9%. The content of 4-methylpiperidine-4-carboxamide without Boc protection increased from <0.05% in the original process to 13.5%. Urea and quaternary carbon isomer amide impurities were generated at 14.6%, and the single-step side reaction rate was 28.1%. Similar impurities were difficult to remove in post-processing and continued to be fed into subsequent processes. The final product yield was 24.6% and the purity was 49.7%. The product yield and purity were severely reduced, and there was no practical industrial application value.

[0123] Comparative Example 4

[0124] Compared with Example 1, the only difference is that steps 2 and 3 are not performed. Instead, ammonia water is directly reacted with Formula 3 for ammonolysis. The amount of ammonia water and the conditions for the amidation reaction are the same as in Example 1.

[0125] The conversion rate of N-Boc-4-methylpiperidine-4-carboxylic acid methyl ester was 43.6%, with the remaining 56.4% consisting of unreacted form 3 and impurities from side reactions. The product purity was low, and simple post-processing could not remove the impurities. Continuing to feed it into subsequent processes, the rearrangement conversion rate was 35.7%, with a large number of side reaction products. The final product yield was 8.7%, and the purity was 32.2%. The product yield and purity were severely reduced, and it had no practical industrial application value.

[0126] Comparative Example 5

[0127] Compared with Example 1, the only difference is that Equation 5 is not used in step 3. All other operations and parameters are the same as in Example 1.

[0128] The N-Boc-4-methylpiperidine-4-carboxylic acid amidation conversion rate was only 73.4%, the HPLC purity of the single-step product was only 57.9%, and the by-product ratio was 27.5%. The product was directly fed into subsequent processes, resulting in a final product yield of 22.4% and a purity of 45.1%. The product yield and purity were severely reduced, and it had no practical industrial application value.

[0129] Comparative Example 6

[0130] Compared with Example 1, the only difference is that in step 4, liquid bromine (Br2) is used to replace formula 9A. The Br element introduced is the same as formula 9A in Example 1, and other operations are the same as in Example 1.

[0131] The 1-Boc-4-methylpiperidine-4-carboxamide rearrangement conversion rate was only 61.2%, with a final single-step conversion rate of only 60.4%, a product purity of only 53.8%, and a total by-product ratio of 41.2%. The product purity and yield were substandard, and it had no practical industrial application value.

[0132] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine, characterized in that the step... include: Step 1: The additives of Formula 1 and Formula 2 and alkyllithium are pre-reacted, followed by the dropwise addition of haloalkane R4X to carry out the alkylation reaction, and the product of Formula 3 is obtained. Formula 1; Formula 2; Formula 3; In Formula 1, R1~R2 are C1~C6 alkyl groups; in Formula 2, R3 is a C1~C6 alkyl group; in R4X, R4 is a C1~C6 alkyl group and X is a halogen. Step 2: The product of Formula 3 was hydrolyzed in an aqueous alcohol solution under the action of an alkali, and then acidified to obtain the product of Formula 4; wherein the volume ratio of alcohol to water in the aqueous alcohol solution was 1~1.2:1; Equation 4; Step 3: Formulas 4, 5, 6, and 7 were pre-reacted, followed by amidation with ammonia to obtain product 8. Formula 5; Formula 6; Formula 7; In Formula 6, R5 is a C1-C4 alkyl group; in Formula 7, R6 is a C1-C4 alkyl group. Formula 8; Step 4: Formula 8 was rearranged in the presence of a base and the assistance of Formula 9 to prepare N-alkoxycarbonyl-4-amino-4-alkylpiperidine of Formula 10. Equation 9; In Formula 9, R7 is a C1~C4 alkyl group; Formula 10.

2. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, In step 1, the reaction solvent for alkylation includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether; Alkyl lithium refers to C1 to C6 alkyl lithium.

3. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, The molar ratio of the additives of Formula 1 and Formula 2 to alkyl lithium is 1:2.1~2.5:1.8~2.2; The molar ratio of Formula 1 and haloalkane R4X is 1:1.8~2.

2.

4. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, The temperature of the pre-reaction process is -20 to -40 ℃; the temperature of adding haloalkanes R4X is -75 to -45 ℃; after the addition of haloalkanes R4X is completed, the temperature is raised to 5 to 40 ℃ and the reaction is stirred. The pre-reaction time is 4-6 h, the dropwise addition time of haloalkane R4X is 1-3 h, and the stirring reaction time after the dropwise addition of haloalkane R4X is completed is 1-2 h.

5. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, In step 2, the alcohol in the alcohol-water solution is a C1-C4 alcohol; The volume ratio of alcohol to water in an aqueous alcohol solution is 1~1.2:1; The alkali mentioned is an alkali metal hydroxide; The molar ratio of the product of Formula 3 to the base is 1:1.8~2.2; The hydrolysis reaction occurs at the reflux temperature.

6. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, The acid used in the acidification process is a strong inorganic acid; The pH at the end of acidification is 3-4.

7. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, In step 3, the solvent for the amidation reaction includes at least one of dichloromethane, 1,2-dichloroethane, and 2-MeTHF; The molar ratios of Equations 4 and 5, and Equations 6 and 7 are 1:1.1~1.3:2.8~3.2:1.8~2.2; The molar ratio of Formula 4 and ammonia is 1:1.8~2.

2.

8. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, In step 3, the pre-reaction temperature is 20~25 ℃, and the time is 2.5~3.5 h; The temperature of ammonia water addition is controlled below 20 ℃, and the reaction is carried out at 20~25 ℃ after the addition is completed.

9. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 1, characterized in that, In step 4, the solvent for the rearrangement reaction includes at least one of acetonitrile, acetone, THF, and 2-MeTHF; The alkali mentioned is an alkali metal hydroxide; The molar ratio of Formula 8, alkali and Formula 9 is 1:4.2~4.8:0.5~0.

6.

10. The method for synthesizing N-alkoxycarbonyl-4-amino-4-alkylpiperidine as described in claim 9, characterized in that, In step 4, the alkali is dissolved in water and cooled to 0-5 °C. Acetonitrile and Formula 8 are added, and the temperature is cooled to -5-0 °C. Formula 9 is then added in batches, and the temperature during the addition process is controlled to be below 0 °C. After Formula 8 is added, the mixture is kept warm and stirred for 0.5-1 h, and then heated to 40-50 °C and reacted for 10-14 h to obtain the N-alkoxycarbonyl-4-amino-4-alkylpiperidine.

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