Synthesis method of 4-(aminomethyl)-4-cyano piperidine-1-carboxylic acid tert-butyl ester

Abstract

The invention discloses a synthesis method of 4-(aminomethyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester, which comprises the following steps: dissolving 4-cyano-piperidine-1-carboxylic acid tert-butyl ester in an organic solvent I, cooling to-80 DEG C to-40 DEG C under the protection of inert gas, slowly adding an alkali solution, stirring and reacting at-80 DEG C to-40 DEG C, adding formaldehyde, naturally heating to room temperature, cooling to-80 DEG C to-40 DEG C, cooling to-80 DEG C to-40 DEG C, and reacting to obtain the 4-(aminomethyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester. The preparation method comprises the following steps: adding tert-butyl carboxylate into a reaction kettle, stirring for reaction, adding an ammonium chloride solution, and stirring for reaction to obtain 4-(aminomethyl)-4-cyano piperidine-1-carboxylic acid tert-butyl ester. According to the invention, 4-cyano piperidine-1-carboxylic acid tert-butyl ester is used as a raw material, and a target compound is prepared through a one-step reaction, so that the synthesis route is greatly shortened, a noble metal catalyst and a highly toxic and dangerous compound are not needed, the reaction conditions are relatively mild, the reaction risk is reduced, and the cost is also reduced. The method disclosed by the invention is relatively high in yield, simple and convenient to operate, simple in post-treatment and purification, and capable of realizing process amplification.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing tert-butyl 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid. Background Technology

[0002] Compound 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester is mainly used as an organic synthesis intermediate in the field of drug development, with the following specific applications: (1) Functional piperidine derivatives can be constructed and used as key intermediates in the synthesis of biologically active piperidine compounds; (2) It can be used for the synthesis of active drug molecules. The amino methyl and cyano groups in the molecule can be further converted into functional groups such as amino and carboxyl groups to construct complex drug molecule skeletons. It is especially suitable for the development of central nervous system or anti-inflammatory drugs. (3) It can be applied to the protection group strategy. The tert-butyl ester group (Boc) provides amino protection function and can withstand catalytic hydrogenation and basic conditions in the synthesis. The protection group can be removed by acidic hydrolysis to achieve selective functional group transformation.

[0003] The existing technology for preparing 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester has disadvantages such as lengthy routes, the need for noble metal catalysts such as Pd / C, the need for highly hazardous reagents such as sodium azide, cumbersome post-processing purification requiring column chromatography, high labor and time costs, unsatisfactory yields, and unsuitability for process scale-up.

[0004] For example, the literature “Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy” (Journal of Medicinal Chemistry 68(2025) 5856 - 5873), the international patent “COMPOUNDS ACTIVE TOWARDS NUCLEAR RECEPTORS” with publication number WO2021124279, and the Chinese patent “Exonucleotide Pyrophosphatase / Phosphodiesterase 1 Inhibitor and Its Preparation and Use” with publication number CN119241496A discloses the preparation of 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester from 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester through a three-step reaction. The synthetic route disclosed in the literature "Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy" is as follows: ; The conditions and yields for each step were as follows: (a) p-Toluenesulfonyl chloride, Et3N, DMAP, and DCM, 0°C to 100°C, overnight, 76%; (b) NaN3 and DMF, 100°C, 1 h, 73%; (c) H2, Pd / C, and CH3CH2OH, 100°C, overnight, 60%. The synthesis of compound 5-5 in Chinese patent CN119241496A uses the same method as in this article, but the yield in step a is lower, only 38%. A similar synthetic method is also disclosed in international patent WO2021124279, using methanesulfonyl chloride as the acyl chloride. The specific synthetic process is as follows: ; However, the above synthesis methods are lengthy, require the use of the precious metal catalyst Pd / C and the highly toxic and hazardous chemical sodium azide, involve some dangerous reaction conditions, have high costs, and result in low overall yields. Although the international patent WO2021124279 has a higher yield, the reaction time is even longer. In step b, iA4-14 is reacted with NaN3 at 100℃ for 2 days, and then NaN3 is added to continue the reaction at 100℃ for 15 hours.

[0005] Furthermore, the paper "Synthesis and biological evaluation of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives for T-type calcium channel blockers" (Bioorganic & Medicinal Chemistry Letters 21 (2011) 5910-5915) discloses the multi-step synthesis of 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester from 4-cyanopiperidine. The synthetic route is as follows: ; The conditions and yields for each step were as follows: (i) under the conditions of Boc2O, TEA and CH2Cl2, reaction from 0°C to room temperature, yield 96%; (ii) under the conditions of ethyl chloroformate, LDA and THF, reaction from -78°C to room temperature, yield 65%; (iii) under the conditions of H2, PtO2 and AcOH, reaction at room temperature, yield 80%; (iv) under the conditions of benzyl chloroformate, NaHCO3 and CH2Cl2, reaction from 0°C to room temperature, yield 92%; (v) under the conditions of NaOH and EtOH / H2O (1:1), reflux, yield 93%; (vi) under the conditions of EDCI, HOBt and DMF, reaction at room temperature, then reaction under 35% NH4OH, yield 94%; (vii) under the conditions of TFAA, pyridine and CH2Cl2, reaction from 0°C to room temperature, yield 77%; (viii) under the conditions of H2, Pd / C and MeOH, reaction at room temperature, yield 83%. This synthetic method also involves lengthy steps and requires the use of noble metals or their oxides as catalysts, resulting in high costs. Therefore, developing a new synthetic method for tert-butyl 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid is of great significance.

[0006] It should be noted that the information disclosed in the background section above is only used to enhance the understanding of the background of this disclosure, and therefore may include information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing tert-butyl 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid, which solves the problems of lengthy routes and the use of precious metal catalysts in existing methods. This invention obtains the target compound in one step, with mild reaction conditions, high yield, and low cost.

[0008] To achieve the above objectives, the present invention provides a method for synthesizing tert-butyl 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid, comprising: ; 4-Cyanopiridine-1-carboxylic acid tert-butyl ester was dissolved in organic solvent I. Under inert gas protection, the temperature was lowered to -80℃ to -40℃, and an alkaline solution was slowly added. The reaction was stirred while maintaining the temperature at -80℃ to -40℃. Formaldehyde was added, and the mixture was allowed to rise naturally to room temperature. The reaction was stirred, and then ammonium chloride solution was added and the reaction was stirred to obtain 4-(aminomethyl)-4-cyanopiridine-1-carboxylic acid tert-butyl ester.

[0009] This invention is based on the nucleophilic addition reaction of formaldehyde by α-cyano carbanion, accompanied by subsequent transformation to form an aminomethyl group. It achieves the efficient synthesis of the target compound in one step, which has significant advantages over the multi-step synthesis methods in the prior art.

[0010] The method of this invention, under low temperature and inert gas protection, involves removing the acidic hydrogen from the α-carbon (the carbon atom adjacent to the cyano group) of 4-cyanopiperidin-1-carboxylic acid tert-butyl ester by acting a base, forming a stable carbanion intermediate. The generated carbanion acts as a nucleophile, attacking the carbonyl carbon atom of formaldehyde (HCHO) to form a new carbon-carbon bond, generating an alkoxy anion intermediate. The reaction system is heated to room temperature and stirred, during which the alkoxy anion is protonated (possibly from the solvent or subsequent quenching), initially generating a 4-cyano-4-(hydroxymethyl)piperidine derivative. During the quenching stage, ammonium chloride solution is added to provide an ammonia source. Under acidic conditions, the hydroxymethyl group may be converted to an aminomethyl group (-CH2NH2) via an imine intermediate, thus forming the final product, namely the target compound 4-(aminomethyl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester.

[0011] Preferably, the organic solvent I is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, n-heptane, diethyl ether, methyl tert-butyl ether, toluene, and ethylbenzene.

[0012] Preferably, in the alkaline solution, the alkali is selected from at least one of sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, and lithium diisopropylamino.

[0013] More preferably, in the alkaline solution, the solvent is selected from at least one of tetrahydrofuran, n-hexane, n-hexane, and toluene.

[0014] Preferably, the molar ratio of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to formaldehyde is 1:1 to 3. More preferably, the molar ratio of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to formaldehyde is 1:1.2 to 2.0.

[0015] Preferably, the molar ratio of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the base is 1:1 to 2. More preferably, the molar ratio of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the base is 1:1.1 to 1.5.

[0016] Preferably, the mass-to-volume ratio of the 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to organic solvent I is 1 g: 5~40 mL. More preferably, the mass-to-volume ratio of the 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to organic solvent I is 1 g: 10~20 mL.

[0017] Preferably, the inert gas is selected from nitrogen and / or argon.

[0018] Preferably, the ammonium chloride solution is a saturated ammonium chloride solution.

[0019] Preferably, the reaction is carried out at room temperature. After the reaction is completed, the reaction solution is post-treated to obtain 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester. The post-treatment method includes: after the reaction is completed, adding water, extracting with organic solvent II, combining the organic phases, washing, drying, and evaporating the organic phases to obtain a crude product; the crude product is purified to obtain 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester. Preferably, the organic solvent II is selected from at least one of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0020] Preferably, the purification is selected from one or more of pulping, column chromatography, and recrystallization. Pulping involves placing the crude product in a suitable solvent and stirring it at a suitable temperature for a certain time to achieve preliminary separation of impurities from the target product. The purified product is then separated by means of filtration or other methods. Column chromatography utilizes the difference in partition coefficients between the stationary and mobile phases to achieve separation. Recrystallization involves first dissolving the crude product in a hot, suitable solvent to prepare a saturated solution, then slowly cooling it. During cooling, the target product gradually crystallizes out, while impurities remain in the mother liquor. These purification methods are known to those skilled in the art and will not be elaborated upon here.

[0021] The method for synthesizing tert-butyl 4-(aminomethyl)-4-cyanopiperidin-1-carboxylic acid of the present invention solves the problems of lengthy routes and the use of noble metal catalysts in existing methods, and has the following advantages: The synthetic method of this invention uses 4-cyanopiperidin-1-carboxylic acid tert-butyl ester as a starting material to prepare 4-(aminomethyl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester in a one-step reaction, significantly shortening the synthetic route. This method eliminates the need for precious metal catalysts and highly toxic and hazardous compounds such as sodium azide, and the reaction conditions are relatively mild, reducing the risks during the reaction process and lowering costs. Furthermore, the synthetic method of this invention offers high yields, is simple to operate, and requires minimal post-processing and purification, allowing for process scale-up and demonstrating greater application prospects and promotional value in organic synthesis fields such as drug development. Attached Figure Description

[0022] Figure 1 The 1H NMR spectrum of 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester prepared in Example 1 of this invention. Detailed Implementation

[0023] 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.

[0024] It should be noted that: Unless otherwise specified in the examples, conditions should be followed according to standard conditions or the manufacturer's recommendations. Instruments whose manufacturers are not specified are all commercially available products. Raw materials and reagents whose manufacturers are not specified are all commercially available goods or can be prepared using known methods.

[0025] In this invention, all features defined in the form of numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are used only for simplicity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0026] The features mentioned in this invention can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification, provided that there is no contradiction in the combination of these features. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0027] In the description of this invention, it should be noted that the terms "comprising," "including," or any other variations thereof are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Those skilled in the art will understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0028] Example 1

[0029] A method for synthesizing tert-butyl 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid, comprising the following steps: ; 4-Cyanopiridine-1-carboxylic acid tert-butyl ester (200.00 g, 951.13 mmol, 1.00 eq) was dissolved in tetrahydrofuran (2.0 L). Under nitrogen protection, the mixture was cooled to -60 °C, and sodium bis(trimethylsilyl)aminocyanate solution (2.0 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) was slowly added dropwise. The mixture was stirred at -60 °C for 30 minutes. Then, formaldehyde (34.27 g, 1.14 mol, 1.20 eq) was added, and the mixture was allowed to rise naturally to room temperature. The mixture was stirred for 12 hours, and then saturated ammonium chloride solution (1.0 L) was added and stirred for 15 minutes.

[0030] After the reaction was complete, water (1.0 L) was added, and the mixture was extracted twice with ethyl acetate (1.5 L × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by slurrying with petroleum ether to obtain the target compound 2, namely 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester, a white solid weighing 225.60 g with a purity of 97% and a yield of 96%.

[0031] The 1H NMR spectrum of (4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester) is as follows: Figure 1 As shown, the characterization data is as follows: 1 H NMR (400 MHz, CDCl3) δ 4.11 (dd, J = 14.3, 7.1 Hz, 2H), 3.00 (s,2H), 2.81 (s, 2H), 1.93 (d, J = 12.4 Hz, 2H), 1.52 - 1.16 (m, 13H).

[0032] Example 2

[0033] The reaction steps are basically the same as in Example 1, except that: The compound yield was 95% when the sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) was replaced with the potassium bis(trimethylsilyl)amino potassium solution (1.0 M base THF solution, 1.05 km mL, 1.05 mol, 1.10 eq).

[0034] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0035] Example 3

[0036] The reaction steps are basically the same as in Example 1, except that: Replacing the sodium bis(trimethylsilyl)amino sodium solution (2.00 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) with the lithium bis(trimethylsilyl)amino lithium solution (1.0 M base THF solution, 1.05 km mL, 1.05 mol, 1.10 eq) yielded a compound yield of 93%.

[0037] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0038] Example 4

[0039] The reaction steps are basically the same as in Example 1, except that: Replacing the sodium bis(trimethylsilyl)amino sodium solution (2.00 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) with the lithium diisopropylamino lithium solution (2.00 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) yielded a compound yield of 94%.

[0040] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0041] Example 5

[0042] The reaction steps are basically the same as in Example 1, except that: Replacing tetrahydrofuran (2.0 L) with 2-methyltetrahydrofuran (2.0 L) resulted in a compound yield of 95%.

[0043] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0044] Example 6

[0045] The reaction steps are basically the same as in Example 1, except that: Replacing tetrahydrofuran (2.0 L) with n-hexane (2.0 L) resulted in a compound yield of 93%.

[0046] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0047] Example 7

[0048] The reaction steps are basically the same as in Example 1, except that: Replacing tetrahydrofuran (2.0 L) with n-heptane (2.0 L) yielded a compound yield of 94%.

[0049] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0050] Example 8

[0051] The reaction steps are basically the same as in Example 1, except that: When formaldehyde (34.27 g, 1.14 mol, 1.20 eq) was replaced with formaldehyde (28.56 g, 951.13 mmol, 1.00 eq), the yield of the compound was 91%.

[0052] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0053] Example 9

[0054] The reaction steps are basically the same as in Example 1, except that: Replacing formaldehyde (34.27 g, 1.14 mol, 1.20 eq) with formaldehyde (57.12 g, 1.90 mol, 2.00 eq) yielded a compound yield of 96%.

[0055] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0056] Example 10

[0057] The reaction steps are basically the same as in Example 1, except that: When formaldehyde (34.27 g, 1.14 mol, 1.20 eq) was replaced with formaldehyde (85.68 g, 2.85 mol, 3.00 eq), the yield of the compound was 94%.

[0058] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0059] Example 11

[0060] The reaction steps are basically the same as in Example 1, except that: The compound yield was 92% when the sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) was replaced with sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 475.56 mL, 951.13 mmol, 1.00 eq).

[0061] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0062] Example 12

[0063] The reaction steps are basically the same as in Example 1, except that: The compound yield was 96% when the sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) was replaced with sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 713.34 mL, 1.43 mol, 1.50 eq).

[0064] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0065] Example 13

[0066] The reaction steps are basically the same as in Example 1, except that: The compound yield was 93% when the sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 523.12 mL, 1.05 mol, 1.10 eq) was replaced with sodium bis(trimethylsilyl)amino sodium solution (2.0 M base THF solution, 951.13 mL, 1.90 mol, 2.00 eq).

[0067] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0068] Example 14

[0069] The reaction steps are basically the same as in Example 1, except that: Replacing -60 °C with -78 °C resulted in a 95% yield of the compound.

[0070] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0071] Example 15

[0072] The reaction steps are basically the same as in Example 1, except that: Replacing -60 °C with -40 °C resulted in a 90% yield of the compound.

[0073] The 1H NMR spectrum data of the obtained product were the same as those in Example 1.

[0074] As can be seen from Examples 1-4, the reactions proceeded smoothly when sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), and lithium diisopropylamino (LDA) were used as bases, respectively. The yields of compound 2 were consistently high, not less than 90%, with the highest yield observed when sodium bis(trimethylsilyl)amino (NaHMDS) was used as the base. Similarly, as can be seen from Examples 1 and 5-7, the reactions proceeded smoothly when tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and n-heptane were used as solvents, respectively. The yields of compound 2 were consistently high, not less than 90%, with the highest yield observed when tetrahydrofuran was used as the solvent. As can be seen from Examples 1 and 8-10, when the molar ratio of compound 1 to formaldehyde is 1.0:(1.00~3.00), the yield of compound 2 is consistently high. Specifically, the product yields at molar ratios of 1.0:1.20 and 1.0:2.00 are essentially equivalent, indicating better reaction performance. As can be seen from Examples 1 and 11-13, when the molar ratio of compound 1 to NaHMDS is 1.0:(1.00~2.00), the yield of compound 2 is consistently high. Specifically, the product yields at molar ratios of 1.0:1.10 and 1.0:1.50 are essentially equivalent, indicating better reaction performance. As can be seen from Examples 1 and 11-13, the reaction performance is further improved when the temperature is lowered to -60 °C.

[0075] In summary, the synthesis method of the present invention achieves efficient preparation of 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester with simple steps and mild conditions. It not only avoids the use of precious metal catalysts and highly toxic and dangerous compounds, reducing reaction hazards and costs, but also significantly shortens the synthetic route and improves the yield through a one-step reaction.

[0076] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A process for the synthesis of tert-butyl 4-(aminomethyl)-4-cyanopiperidine- 1 -carboxylate, characterized in that, The method comprises the following steps: ； The 4-cyanopiperidine-1-carboxylic acid tert-butyl ester is dissolved in an organic solvent I, under inert gas protection, cooled to-80~ -40℃, slowly added with a base solution, kept stirring at-80~ -40℃, added with formaldehyde, naturally raised to room temperature, stirred, added with an ammonium chloride solution, stirred, to obtain 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester.

2. The method of synthesis of claim 1, wherein, The organic solvent I is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, n-heptane, diethyl ether, methyl tert-butyl ether, toluene and ethylbenzene.

3. The method of synthesis of claim 1, wherein, The base in the base solution is at least one selected from sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide and lithium diisopropylamide.

4. The method of synthesis of claim 3, wherein, The solvent in the base solution is at least one selected from tetrahydrofuran, n-hexane, n-ethane and toluene.

5. The method of synthesis of claim 1, wherein, The molar ratio of the 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to formaldehyde is 1:1~3; Or / and, the molar ratio of the 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the base is 1:1~2.

6. The method of synthesis of claim 1, wherein, The mass-volume ratio of the 4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the organic solvent I is 1 g:5~40 mL.

7. The method of synthesis of claim 1, wherein, The inert gas is selected from nitrogen and / or argon.

8. The method of synthesis according to any one of claims 1 to 7, wherein, The reaction at room temperature is ended, the reaction liquid is treated, to obtain 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester; The method of the treatment comprises: After the reaction is ended, water is added, extracted with an organic solvent II, the organic phases are combined, the organic phase is washed, dried, rotary evaporated, to obtain a crude product; The crude product is purified, to obtain 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester.

9. The method of synthesis of claim 8, wherein, The organic solvent II is at least one selected from ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

10. The method of synthesis of claim 8, wherein, The purification is selected from any one or two or more ways of beating, column chromatography and recrystallization.

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