阅读说明：本技术 一种N-Boc-4-哌啶甲酸的制备方法 (Preparation method of N-Boc-4-piperidinecarboxylic acid ) 是由 杨卫华 李晶 张利坤 谈聪 金力 葛文强 王云 李淦如 俞丽燕 倪建洲 华超 于 2021-08-25 设计创作，主要内容包括：本发明公开了一种N-Boc-4-哌啶甲酸的制备方法,包括如下步骤：将4-哌啶甲酸加入乙醇中,室温滴加Boc酸酐,搅拌反应至溶清,继续室温反应至点板无原料；蒸发溶剂至体系呈粘稠状态后停止,加水打浆,然后过滤,将滤饼干燥。其中,4-哌啶甲酸、Boc酸酐和乙醇质量比为100：169-185：450-550。4-哌啶甲酸采用如下工艺制取：将4-氰基吡啶进行酶催化水解得到吡啶-4-甲酸；将吡啶-4-甲酸进行高压氢化得到4-哌啶甲酸。(The invention discloses a preparation method of N-Boc-4-piperidinecarboxylic acid, which comprises the following steps: adding 4-piperidinecarboxylic acid into ethanol, dropwise adding Boc anhydride at room temperature, stirring for reaction until the solution is clear, and continuing to react at room temperature until no raw material is added on the spot plate; evaporating the solvent until the system is viscous, adding water, pulping, filtering, and drying the filter cake. Wherein the mass ratio of the 4-piperidinecarboxylic acid to the Boc anhydride to the ethanol is 100: 169-185: 450-550. The 4-piperidine formic acid is prepared by adopting the following process: carrying out enzyme catalytic hydrolysis on 4-cyanopyridine to obtain pyridine-4-formic acid; the pyridine-4-formic acid is hydrogenated under high pressure to obtain the 4-piperidine formic acid.)

1. A preparation method of N-Boc-4-piperidinecarboxylic acid is characterized by comprising the following steps: adding 4-piperidinecarboxylic acid into ethanol, dropwise adding Boc anhydride at room temperature, stirring for reaction until the solution is clear, and continuing to react at room temperature until no raw material is added on the spot plate; evaporating the solvent until the system is viscous, adding water, pulping, filtering, and drying the filter cake.

2. The method for preparing N-Boc-4-piperidinecarboxylic acid as claimed in claim 1, wherein the mass ratio of 4-piperidinecarboxylic acid, Boc anhydride and ethanol is 100: 169-185: 450-550.

3. The method of claim 1, wherein the 4-piperidinecarboxylic acid is prepared by the following steps: carrying out enzyme catalytic hydrolysis on 4-cyanopyridine to obtain pyridine-4-formic acid; the pyridine-4-formic acid is hydrogenated under high pressure to obtain the 4-piperidine formic acid.

4. The process of claim 3, wherein the N-Boc-4-piperidinecarboxylic acid is enzymatically catalyzed by a cyano hydrolase.

5. The process according to claim 4, wherein the mass ratio of 4-cyanopyridine to immobilized enzyme in S1 is 1.8-2.2: 1.

6. the process of claim 3, wherein the temperature of the enzymatic hydrolysis is 35-36 ℃ and the time of the enzymatic hydrolysis is 4 ± 0.5 hours.

7. The process according to claim 3, wherein the pH of the reaction system during the enzymatic hydrolysis in S1 is maintained at 7.3. + -. 0.2.

8. The process of claim 3, wherein the hydrogenation is carried out under high pressure using a ruthenium on carbon catalyst.

9. The process of claim 3, wherein the high pressure hydrogenation is carried out by: adding the liquid obtained by enzyme catalysis and a ruthenium-carbon catalyst into an autoclave, stirring, heating to 120 ℃ for reaction until no hydrogen is absorbed, continuing the reaction for at least 2 hours, cooling and discharging, and spotting the plate without fluorescence; evaporating to dry, washing with ethanol, filtering, oven drying the filter cake, and mixing the filtrates.

10. The method for preparing N-Boc-4-piperidinecarboxylic acid according to claim 8 or 9, wherein the mass ratio of pyridine-4-carboxylic acid to ruthenium-carbon catalyst is 14-16: 1.

Technical Field

The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation method of N-Boc-4-piperidinecarboxylic acid.

Background

N-Boc-4-piperidinecarboxylic acid, also known as 1-Boc-4-piperidinecarboxylic acid, has a molecular weight of 229.273, a CAS number of 84358-13-4, and a molecular formula of C₁₁H₁₉NO₄It is a white solid compound. N-Boc-4-piperidine formic acid is used as a drug intermediate to prepare 4-piperidine ethyl formate, and 4-piperidine ethyl formate is also an important piperidine derivative drug intermediate and is mainly applied to synthesis of drugs for various neurological diseases, such as convulsion, anti-epilepsy, tranquilization and the like.

The N-Boc-4-piperidinecarboxylic acid can be prepared by reacting 4-piperidinecarboxylic acid with Boc anhydride. The prior art discloses that:

4-Piperidinecarboxylic acid (1g,7.74mmol) was dissolved in NaOH solution (2M,10mL), a solution of Boc anhydride (2.53g,11.61mmol) in THF (10mL) was slowly added under ice-bath conditions, the reaction was stirred at room temperature for 1 hour, THF was removed using a rotary evaporator, the aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid, then extracted with ethyl acetate, and the combined organic phasesAnhydrous Na for phase₂SO₄Drying and filtration, concentration of the filtrate on a rotary evaporator and drying under vacuum gave the compound N-Boc-4-piperidinecarboxylic acid as a white solid (1.78g,7.76mmol, 100% yield).

However, the technical route disclosed in the prior art is complex in reaction, and is easy to cause pollution because dilute hydrochloric acid, tetrahydrofuran, ethyl acetate and other substances are required.

Disclosure of Invention

The invention aims to solve the defects in the prior art and provides a preparation method of N-Boc-4-piperidinecarboxylic acid.

A preparation method of N-Boc-4-piperidinecarboxylic acid comprises the following steps:

carrying out enzyme catalytic hydrolysis on 4-cyanopyridine to obtain pyridine-4-formic acid;

carrying out high-pressure hydrogenation on pyridine-4-formic acid to obtain 4-piperidinecarboxylic acid;

adding 4-piperidinecarboxylic acid into ethanol, dropwise adding Boc anhydride at room temperature, stirring for reaction until the solution is clear, and continuing to react at room temperature until no raw material is added on the spot plate; evaporating the solvent until the system is viscous, adding water, pulping, filtering, and drying the filter cake.

The synthetic route is as follows:

preferably, the enzyme catalysis is carried out in an immobilized enzyme with a cyano hydrolase.

Preferably, the mass ratio of the 4-cyanopyridine to the immobilized enzyme is 1.8-2.2: 1.

preferably, the temperature of the enzymatic hydrolysis is 35-36 ℃ and the time of the enzymatic hydrolysis is 4 + -0.5 hours.

Preferably, the pH value of the system is maintained to be 7.3 +/-0.2 during the enzymatic hydrolysis process.

Preferably, a ruthenium on carbon catalyst is used in the high pressure hydrogenation process.

Preferably, the specific operation of the high-pressure hydrogenation is as follows: adding the liquid obtained by enzyme catalysis and a ruthenium-carbon catalyst into an autoclave, stirring, heating to 120 ℃ for reaction until no hydrogen is absorbed, continuing the reaction for at least 2 hours, cooling and discharging, and spotting the plate without fluorescence; evaporating to dry, washing with ethanol, filtering, oven drying the filter cake, and mixing the filtrates.

Preferably, the mass ratio of the pyridine-4-carboxylic acid to the ruthenium carbon catalyst is 14-16: 1.

preferably, the mass ratio of the 4-piperidinecarboxylic acid to the Boc anhydride to the ethanol is 100: 169-185: 450-550.

The method has simple reaction conditions, and only adopts 4-piperidine formic acid and Boc anhydride to carry out room temperature reaction in absolute ethyl alcohol to obtain the N-Boc-4-piperidine formic acid. Meanwhile, the 4-piperidinecarboxylic acid is synthesized by adopting a new technical route, so that the synthesis method is simpler, more convenient and faster, and is more energy-saving and emission-reducing.

Drawings

FIG. 1 is a schematic structural diagram of a beater in the beating process of the preparation method of N-Boc-4-piperidinecarboxylic acid of the invention.

In the figure: 1. a base; 2. a pulping tank; 3. a mounting frame; 4. a motor; 5. a first fixing frame; 6. a rotating shaft; 7. a shaft sleeve; 8. a limiting fixing plate; 9. a first separation chamber; 10. a second separation chamber; 11. a filter screen; 12. a centrifugal leaf; 13. a liquid separation hole; 14. a second fixing frame; 15. a limiting fixing plate; 16. a third fixing frame; 17. mounting a plate; 18. a roller; 19. a limiting shaft sleeve; 20. a fixed shaft; 21. a sealing door mount; 22. a sealing door; 23. a handle; 24. a second discharge pipe; 25. a first discharge pipe; 26. a third discharge pipe; 27. a discharge valve; 28. mounting the cylinder; 29. a piston; 30. a piston shaft; 31. a spring.

Detailed Description

The present invention will be further illustrated with reference to the following specific examples.

Example 1

Adding 150g of 4-cyanopyridine into 1800g of water, adding 75g of immobilized enzyme, and carrying out enzymatic hydrolysis for 4 hours to obtain pyridine-4-formic acid, wherein the temperature of the enzymatic hydrolysis is 35-36 ℃, and the cyano hydrolase is used as the immobilized enzyme.

In this embodiment 1, as shown in fig. 1, a beater used in a beating process includes a base 1, an upper end of the base 1 is provided with a mounting frame 3, an upper end of the base 1 is further provided with a beating tank 2, a first fixing frame 5 is connected between the mounting frame 3 and the beating tank 2, one side of the mounting frame 3 is provided with a motor 4, one side of the motor 4 close to the beating tank 2 is provided with a rotating shaft 6, the rotating shaft 6 extends into the beating tank 2 and is provided with a plurality of centrifugal blades 12 inside the beating tank 2, the centrifugal blades 12 are provided with a plurality of liquid separating holes 13, the rotating shaft 6 is driven by the motor 4 to rotate, the rotating shaft 6 rotates to drive the centrifugal blades 12 to rotate so as to stir materials inside the beating tank 2, a filter screen 11 is arranged inside the beating tank 2, the filter screen 11 divides the beating tank 2 into a first separating cavity 9 and a second separating cavity 10, a first discharging pipe 25 is connected between the first separating cavity 9 and the outside, and a second discharging pipe 24 is connected between the second separating cavity 10 and the outside, solid particles in the beating process remain in the second separation cavity 10, liquid enters the first separation cavity 9 after being filtered by the filter screen 11 and is finally discharged by the first discharge pipe 25, the solid particles can be discharged from the second discharge pipe 24, in addition, the materials to be pulped can enter through the limiting fixing plate 8, the inner wall of the pulping tank 2 is also provided with a plurality of second fixing frames 14, a limit fixing plate 15 is connected between the second fixing frames 14 and the filter screen 11, the structural stability of the filter screen 11 in the centrifugal process is ensured, the end part of the pulping tank 2 is provided with a sealing door mounting seat 21, the sealing door mounting seat 21 is provided with a sealing door 22, the sealing door 22 is provided with a handle 23, thereby facilitating the cleaning of the first separation cavity 9, and a third discharging pipe 26 is arranged at the end part of the pulping tank 2 far away from the motor 4, and a discharging valve 27 is arranged on the third discharging pipe 26.

It can be understood that, in order to improve centrifugal stability, third mount 16 has still been set up at the making beating jar 2 inner wall, is provided with spacing axle sleeve 19 on the third mount 16, and the one end that pivot 5 is close to spacing axle sleeve 19 is equipped with fixed axle 20, and fixed axle 20 runs through spacing axle sleeve 19 and sets up, and the tip of spacing axle sleeve 19 is provided with mounting panel 17, and one side that mounting panel 17 is close to third mount 16 is provided with gyro wheel 18, so can guarantee the stability of pivot 5 rotation.

It can be understood, for the process that makes the making beating more stable, set up installation section of thick bamboo 28 in base 1 upper end, set up piston 29 in the installation section of thick bamboo 28, one side that piston 29 is close to beating jar 2 is provided with piston shaft 30, piston shaft 30 is fixed on beating jar 2's outer wall, and piston shaft 30's periphery has cup jointed spring 31, and spring 31 is located installation section of thick bamboo 28, so can effectively improve the stability when beating jar 2 uses, has avoided producing very big noise.

It can be understood that by using the special beater in the beating process, the raw materials can be mixed and impurities can be removed more thoroughly, the synthesis process is ensured to be carried out more thoroughly and efficiently, the obtained product has better purity and better yield.

Example 2

Removing immobilized enzyme from the liquid obtained by the enzyme catalysis in the embodiment 1, adding the liquid and ruthenium-carbon catalyst into an autoclave, stirring, heating to 120 ℃, reacting until hydrogen is not absorbed, continuing to react for at least 2 hours, cooling, discharging, and making the spot plate have no fluorescence; evaporating to dry, washing with ethanol, filtering, oven drying the filter cake, and mixing the filtrates.

Wherein the addition amount of pyridine-4-carboxylic acid was 150g (calculated from the concentration of the liquid obtained by the enzyme catalysis in example 1), and the addition amount of the ruthenium charcoal catalyst was 10 g.

4 batches were carried out according to the above procedure with the following results:

the sum of the dry product and the combined filtrate in each batch was 399.3g, while 419.5g could theoretically be collected, so the yield was 95.18%.

Example 3

Adding 100g of 4-piperidinecarboxylic acid into 500g of ethanol, dropwise adding 177g of Boc anhydride at room temperature, stirring for reaction until the mixture is clear, and continuing to react at room temperature until no raw material is added on the spot plate; evaporating the solvent to separate out white solid, stopping evaporation until the system is in a viscous state, adding 500g of water for pulping, then filtering, and drying the filter cake.

The bench test is carried out in 3 batches according to the steps, and the results are as follows:

batches of	Finished dry product/g	Theory/g	Yield/%	Purity/%)	Maximum single impurity/%)
						1	171.6	177.5	96.6	99.11	0.25
2	172.6	177.5	97.2	99.25	0.35
						3	173.3	177.5	97.6	99.43	0.33

Example 4

Adding 20g of 4-piperidinecarboxylic acid into 100g of ethanol, dropwise adding 35.5g of Boc anhydride at room temperature, stirring for reaction until the mixture is clear, and continuing to react at room temperature until no raw material exists on the spot plate; evaporating the solvent to separate out white solid, stopping evaporation until the system is in a viscous state, adding 100g of water for pulping, then filtering, and drying the filter cake.

Comparative example

Adding 20g of 4-piperidinecarboxylic acid into 100g of methanol, dropwise adding 35.5g of Boc anhydride at room temperature, stirring for reaction until the mixture is clear, and continuing to react at room temperature until no raw material exists on the spot plate; the solvent was evaporated until the system became viscous, and then 100g of water was added for beating, followed by filtration, and the filter cake was dried.

The finished products obtained in example 4 and the comparative example were tested, and the results are as follows:

through the comparison, it can be found that: example 4 using ethanol as solvent, although the yield is lower than the comparative example, the purity is higher than the comparative example, and the maximum single impurity ratio is lower, and is more suitable for being used as a drug intermediate.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.