CN116514703A - Method for reductive amination of N-tert-butoxycarbonyl-4-piperidone and N-tert-butoxycarbonyl-4-dimethylaminopiperidone - Google Patents

Abstract

The application relates to the field of reductive amination methods, and specifically discloses a method for reductive amination of N-tert-butoxycarbonyl-4-piperidone and N-tert-butoxycarbonyl-4-dimethylaminopiperidone. The method of the present application comprises the following steps: step S1, mixing the organic solvent, N-tert-butoxycarbonyl-4-piperidone and dimethylamine methanol to obtain a raw material liquid; and loading the catalyst into a fixed hydrogenation bed; step S2 , the raw material liquid is pumped into a fixed hydrogenation bed to react, the pressure is 2-2.5MPa, the temperature is 50-100°C, the raw material flow rate is 0.1-1.6L/min, the hydrogen flow rate is 5-30L/min, and the hydrogenated liquid is obtained; step S3, the The hydrogenation solution is concentrated under reduced pressure until solids are precipitated; step S4: then mixed with ethanol, and the ethanol is heated and evaporated to obtain the product. The method for reductive amination of N-tert-butoxycarbonyl-4-piperidone of the present application has the effects of simplified steps, less harmful waste, fast reaction speed and large reaction volume at one time.

Description

A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone and N-tert-butoxycarbonyl yl-4-dimethylaminopiperidone

technical field

This application relates to the field of reductive amination methods, more specifically, it relates to a method for reductive amination of N-tert-butoxycarbonyl-4-piperidone and N-tert-butoxycarbonyl-4-dimethylaminopiperone pyridone.

Background technique

Reductive amination reaction is a simple method to convert aldehydes and ketones into amines; N-tert-butoxycarbonyl-4-piperidone is a widely used pharmaceutical intermediate, usually N-tert-butoxycarbonyl- After the reductive amination of 4-piperidone, the next step of drug synthesis can be carried out.

In related technologies, sodium cyanoborocyanide and sodium triacetoxyborohydride are new reductive amination reagents developed in recent years with good universality and selectivity. The English abbreviation of sodium triacetoxyborohydride is For STAB-H, it is prepared by sodium borohydride and acetic acid in benzene or N,N-dimethylacetamide. The reductive amination reaction conditions of STAB-H are mild, the catalytic reduction performance is good, and it is easy to separate and purify. The catalyst itself and by-products are non-toxic, and there is no pollution to the environment. Since there is only one hydride ion in the STAB-H structure, the dosage can be obtained relatively Strict control makes it the preferred catalyst for reductive amination reaction. The chemical equation for the reductive amination of N-tert-butoxycarbonyl-4-piperidone by sodium triacetoxyborohydride is as follows:

The reductive amination process of sodium triacetoxyborohydride is as follows: 1. Add N-tert-butoxycarbonyl-4-piperidone, sodium triacetoxyborohydride and tetrahydrofuran in sequence to a batch kettle, Insulation and pressure reaction; 2. After the central control is qualified, control the temperature at 5-25°C, add water to the system to quench the reaction, and stir; 3. Concentrate to remove tetrahydrofuran; 4. Add water to dissolve and separate out solid salt; 5. Dichloromethane Add solid salt and extract 5 times; 6. Wash the organic phase with aqueous sodium chloride solution; 7. Remove water with anhydrous magnesium sulfate and press filter; 8. Concentrate and remove solvent until viscous; 9. Add n-heptane for beating and centrifuge; 10. Dry.

The above-mentioned related technology uses sodium triacetoxyborohydride as a reductive amination reagent. After the reaction, steps such as quenching, concentration, dilution, salt formation, extraction, salt washing, and solvent removal are required. The post-treatment is cumbersome and will generate a large amount of The three wastes have serious pollution problems.

Contents of the invention

In order to simplify the steps of reductive amination of N-tert-butoxycarbonyl-4-piperidone and reduce the discharge of three wastes, the application provides a method for reductive amination of N-tert-butoxycarbonyl-4-piperidone and N-tert-butoxycarbonyl-4-dimethylaminopiperidone.

In the first aspect, a method for reductive amination of N-tert-butoxycarbonyl-4-piperidone provided by the present application adopts the following technical scheme:

A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone, comprising the following steps:

Step S1: mixing an organic solvent, N-tert-butoxycarbonyl-4-piperidone and dimethylamine methanol to obtain a raw material liquid; and loading the catalyst into a fixed hydrogenation bed;

Step S2, pumping the raw material liquid into a fixed hydrogenation bed for reaction at a pressure of 2-2.5 MPa, a temperature of 50-100°C, a raw material flow rate of 0.1-1.6 L/min, and a hydrogen flow rate of 5-30 L/min to obtain a hydrogenated liquid;

Step S3: concentrating the hydrogenation solution under reduced pressure until solids are precipitated to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone;

Step S4: Mix the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone with ethanol, and heat and distill the ethanol to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidone, That is, the product of N-tert-butoxycarbonyl-4-piperidone reductive amination; the chemical equation of reductive amination N-tert-butoxycarbonyl-4-piperidone is as follows:

By adopting the above technical scheme and using fixed-bed hydrogenation technology to carry out the reductive amination reaction of N-tert-butoxycarbonyl-4-piperidone, the post-treatment steps only need two steps of concentration and distillation with ethanol to obtain a purity as high as 99.8%. Compared with the traditional reductive amination method, the N-tert-butoxycarbonyl-4-dimethylaminopiperidone has simplified steps and fewer harmful wastes.

And the above reaction is carried out in a fixed hydrogenation bed. Compared with the traditional reaction in a batch kettle, there is no safety problem of high pressure and high temperature, and the amount of feeding at one time is much larger than that of the batch kettle. It is a safe and efficient green Hydrogenation technology has the advantages of accelerating reaction speed, reducing reactor volume, improving reaction selectivity, avoiding catalyst separation, improving safety, and continuous automation. It is expected to overturn the current situation of extensive production of fine chemicals and achieve a leapfrog improvement in production technology .

Optionally, the raw material liquid includes the following components in parts by weight: 9.5-11.5 parts of organic solvent, 19-23 parts of N-tert-butoxycarbonyl-4-piperidone, 0.9-1 part of dimethylamine methanol and 0.01 -0.03 part catalyst.

By adopting the above technical scheme, the organic solvent is used to dissolve N-tert-butoxycarbonyl-4-piperidone and dimethylamine methanol, and the configuration is in a liquid state. The catalyst is added to the fixed hydrogenation bed in advance, and the raw materials can be treated during the whole reaction process. The liquid is fully catalyzed; when the reaction liquid is reacted in the hydrogenation bed, the reaction is relatively thorough, so that the yield of N-tert-butoxycarbonyl-4-dimethylaminopiperidone finally obtained is as high as 95.3%, and the purity is as high as 99.8% %.

Optionally, the catalyst is Pd/C, Pt/C, Rh/C, Ir/C, Ru/C or Os/C.

By adopting the above-mentioned technical scheme, the above-mentioned catalysts are commonly used catalysts, are cheap and easy to obtain, and facilitate the industrial application of the N-tert-butoxycarbonyl-4-dimethylaminopiperidone reductive amination method of the present application.

Optionally, the organic solvent is methanol, ethanol or isopropanol.

By adopting the above-mentioned technical scheme, the above-mentioned organic solvents are all cheap and easy to obtain organic solvents, which facilitates the industrial application of the N-tert-butoxycarbonyl-4-dimethylaminopiperidone reductive amination method of the present application.

Optionally, in the step S1, after mixing the organic solvent, N-tert-butoxycarbonyl-4-piperidone and dimethylamine methanol, a step of filtering impurities is also included to finally obtain a raw material solution.

By adopting the above technical scheme, the purpose of filtering impurities is to filter out other solid impurities in the reaction raw materials, so that the reaction raw materials are pure, and the prepared N-tert-butoxycarbonyl-4-dimethylaminopiperidone has a purity of up to 99.8%. .

Optionally, in the step S3, the hydrogenation solution is concentrated under reduced pressure at a temperature of 50-60°C and a pressure less than -70KPa until solids are precipitated to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylamino piperidone.

By adopting the above technical scheme, the purpose of concentrating under reduced pressure at 50-60°C is to speed up the speed of concentrating under reduced pressure without destroying the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone , to improve the overall response speed.

Optionally, in the step S4, the volume ratio of the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone to ethanol is 1:(9-11).

By adopting the above-mentioned technical scheme, the proportioning of the N-tert-butoxycarbonyl-4-dimethylaminopiperidone and ethanol that is suitable for preliminary treatment makes ethanol not produce waste, and the N-tert-butyl Oxycarbonyl-4-dimethylaminopiperidone doped impurities were carried away in the greatest amount.

Optionally, in the step S4, the temperature for distilling ethanol by heating is 50-60°C.

By adopting the above-mentioned technical scheme, heating and distilling ethanol, so that ethanol can take away other substances except N-tert-butoxycarbonyl-4-dimethylaminopiperidone faster, and speed up the purification of N-tert-butoxycarbonyl-4 - The speed of dimethylaminopiperidone, to speed up the overall reaction efficiency.

In the second aspect, the application provides a kind of N-tert-butoxycarbonyl-4-dimethylaminopiperidone, which adopts the following technical scheme: a kind of N-tert-butoxycarbonyl-4-dimethylaminopiperidone is obtained by the above-mentioned method prepared.

By adopting the above-mentioned technical scheme, the yield of N-tert-butoxycarbonyl-4-dimethylaminopiperidone obtained by the above-mentioned preparation method is 95.3%, the purity is 99.8%, and the PMI is 16.5. The yield and purity are far greater than The yield and purity of N-tert-butoxycarbonyl-4-dimethylaminopiperidone prepared by traditional technology; PMI is far less than that of N-tert-butoxycarbonyl-4-dimethylaminopiperidone prepared by traditional technology The PMI; Prove, the preparation method of the present application can produce the better quality N-tert-butoxycarbonyl-4-dimethylaminopiperidone.

In summary, the application has the following beneficial effects:

1. In this application, the reductive amination reaction of N-tert-butoxycarbonyl-4-piperidone is carried out using fixed-bed hydrogenation technology. The post-processing steps only need two steps of concentration and ethanol steaming, and the purity can be as high as 99.8%. Compared with the traditional reductive amination method, the N-tert-butoxycarbonyl-4-dimethylaminopiperidone has simplified steps, less harmful waste, fast reaction speed and large reaction volume at one time; 2. The reduction method of the present application In the amination method, the purpose of concentrating under reduced pressure at 50-60°C is to speed up the concentration under reduced pressure without destroying the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone. Improve the overall response speed;

3. The yield of N-tert-butoxycarbonyl-4-dimethylaminopiperidone prepared by the method of the present application is 95.3%, the purity is 99.8%, and the PMI is 16.5, which is far superior to the N-butoxycarbonyl-4-dimethylaminopiperidone prepared by traditional techniques. - Yield, purity and PMI of tert-butoxycarbonyl-4-dimethylaminopiperidone.

Description of drawings

Figure 1 is intended to show the liquid chromatogram of N-tert-butoxycarbonyl-4-dimethylaminopiperidone prepared in Example 3.

Detailed ways

The present application will be described in further detail below in conjunction with examples and comparative examples.

The sources of raw materials for the following examples and comparative examples are provided: the raw materials for the examples and comparative examples are all commercially available.

A kind of embodiment of the method of reductive amination N-tert-butoxycarbonyl-4-piperidone

Example 1

A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone, comprising the following steps:

Step S1: Mix 9.5kg of isopropanol, 23kg of N-tert-butoxycarbonyl-4-piperidone, and 0.9kg of dimethylamine methanol, and filter to remove solid impurities to obtain a raw material solution; then 0.03kg of catalyst Rh/C Add fixed bed catalyst;

Step S2: Pump the raw material liquid into the fixed hydrogenation bed for reaction, set the pressure at 2 MPa, the temperature at 100°C, the raw material flow rate at 0.1 L/min, and the hydrogen flow rate at 30 L/min to obtain the hydrogenated liquid;

Step S3: Concentrate the hydrogenation solution under reduced pressure at 50°C and a pressure of -60KPa until solids are precipitated to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone;

Step S4: Mix the pre-treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone with ethanol, wherein the volume of the pre-treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone and ethanol The ratio is 1:9; then the ethanol is heated and distilled off at 50°C to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidone, that is, the reductive amination of N-tert-butoxycarbonyl-4-piperidone The product; The chemical equation of reductive amination N-tert-butoxycarbonyl-4-piperidone is as follows:

Example 2

A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone, comprising the following steps:

Step S1: Mix 11.5kg ethanol, 19kg N-tert-butoxycarbonyl-4-piperidone, and 1kg dimethylamine methanol evenly, filter to remove solid impurities, and obtain a raw material solution; then add 0.01kg catalyst Pt/C to the fixed bed catalyst;

Step S2: Pump the raw material liquid into the fixed hydrogenation bed for reaction, set the pressure at 2.5MPa, the temperature at 50°C, the raw material flow rate at 1.6L/min, and the hydrogen flow rate at 5L/min to obtain the hydrogenated liquid;

Step S3: Concentrate the hydrogenation solution under reduced pressure at 60°C and a pressure of -40KPa until solids are precipitated to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone;

Step S4: Mix the pre-treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone with ethanol, wherein the volume of the pre-treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone and ethanol The ratio is 1:11; then the ethanol is heated and distilled off at 60°C to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidone, that is, the reductive amination of N-tert-butoxycarbonyl-4-piperidone The product; The chemical equation of reductive amination N-tert-butoxycarbonyl-4-piperidone is as follows:

Example 3

A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone, comprising the following steps:

Step S1: Mix 10.6kg of methanol, 21kg of N-tert-butoxycarbonyl-4-piperidone, and 0.905kg of dimethylamine methanol, and filter to remove solid impurities to obtain a raw material solution; then add 0.01kg of catalyst Pd/C to fix bed catalyst;

Step S2: Pump the raw material liquid into the fixed hydrogenation bed for reaction, set the pressure at 2.3MPa, temperature at 70°C, raw material flow rate at 1L/min, hydrogen flow rate at 15L/min, to obtain hydrogenated liquid;

Step S3: Concentrate the hydrogenation solution under reduced pressure at 55°C and a pressure of -60KPa until solids are precipitated to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone;

Step S4: Mix the pre-treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone with ethanol, wherein the volume of the pre-treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone and ethanol The ratio is 1:10.6; then the ethanol is heated and evaporated at 60°C to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidone, that is, the reductive amination of N-tert-butoxycarbonyl-4-piperidone The product; The chemical equation of reductive amination N-tert-butoxycarbonyl-4-piperidone is as follows:

Comparative example 1

The difference from embodiment 3 is that step S2 is different, and the specific steps are as follows;

Step S2: Pump the raw material liquid into the fixed hydrogenation bed for reaction, set the pressure at 5 MPa, the temperature at 150°C, the raw material flow rate at 0.05 L/min, and the hydrogen flow rate at 50 L/min to obtain hydrogenated liquid.

Comparative example 2

The difference from embodiment 3 is that step S2 is different, and the specific steps are as follows;

Step S2: Pump the raw material solution into the fixed hydrogenation bed for reaction, set the pressure at 0.5 MPa, the temperature at 30°C, the raw material flow rate at 5 L/min, and the hydrogen flow rate at 1 L/min to obtain a hydrogenated liquid.

Comparative example 3

The difference from embodiment 3 is that step S1 is different, and the specific steps are as follows;

Step S1: Mix 20kg of methanol, 12kg of N-tert-butoxycarbonyl-4-piperidone, and 3kg of dimethylamine methanol evenly, filter to remove solid impurities, and obtain a raw material solution; then add 0.005kg of catalyst Pd/C to the fixed-bed catalyst .

Comparative example 4

The difference from embodiment 3 is that step S1 is different, and the specific steps are as follows;

Step S1: Mix 5kg of methanol, 30kg of N-tert-butoxycarbonyl-4-piperidone, and 0.5kg of dimethylamine methanol, and filter to remove solid impurities to obtain a raw material solution; then add 0.06kg of catalyst Pd/C to the fixed bed catalyst.

Comparative example 5

A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone, comprising the following steps:

1. Add 21kg of N-tert-butoxycarbonyl-4-piperidone, 21kg of sodium triacetoxyborohydride, 10.6kg of tetrahydrofuran and 0.0225kg of hydrochloric acid with a concentration of 12mol/L into the batch kettle in sequence, and heat at 20°C. Pressure reaction for 72 hours; 2. Control the temperature at 20°C, add 5 times the volume of water to the system to quench the reaction, and stir evenly; 3. Concentrate and remove THF at 55°C and a pressure of -60KPa; 4. Add to 3 Add 5 times the volume of water to the obtained product to dissolve and separate the solid salt; 5. Add dichloromethane to the solid salt and extract 5 times to obtain an organic phase. The weight ratio of dichloromethane to solid salt is 10:1; 6. Use sodium chloride aqueous solution to wash the organic phase, the volume ratio of organic phase to sodium chloride aqueous solution is 1:2; 7, use 3g of anhydrous magnesium sulfate to remove water, press filter; 8, at 55°C, under the pressure of -60KPa Concentrate to remove the solvent until it becomes viscous; 9, add n-heptane to make a slurry, and centrifuge; 10, dry to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidone.

performance test

The N-tert-butoxycarbonyl-4-dimethylaminopiperidone prepared in Examples 1 to 3 and Comparative Examples 1 to 5 was used for performance testing, detection yield, purity and PMI;

Detection basis: yield=(reaction product/reaction raw material)×100%;

Purity is detected by liquid chromatography: calculate the percentage of N-tert-butoxycarbonyl-4-dimethylaminopiperidone peak area in the total product peak area;

PMI: the ratio of the sum of the mass of all substances in the whole process of product production to the mass of the target product;

The test results are shown in Table 1; the product liquid chromatogram of Example 3 is also shown in the accompanying drawing 1 of the description;

Table 1

Yield (%) purity(%) PMI Example 1 95.2 99.7 17.4 Example 2 95.1 99.8 17.8 Example 3 95.3 99.8 16.5 Comparative example 1 93.4 99.5 28 Comparative example 2 92.7 99.5 31 Comparative example 3 93.6 99.6 25 Comparative example 4 94.5 99.7 twenty three Comparative example 5 90.5 99.5 68

In conjunction with embodiment 1,2 and embodiment 3, it can be seen that the reaction conditions and reaction raw material consumption of embodiment 1,2,3 are all different, but all within the protection scope of the application, embodiment 1,2,3 system The obtained N-tert-butoxycarbonyl-4-dimethylaminopiperidone yield and purity are higher, and the PMI is lower; and the N-tert-butoxycarbonyl-4-dimethylaminopiperidine obtained in Example 3 Ketone yield and purity are the highest, and PMI is the lowest; therefore, the reaction conditions and raw material consumption of embodiment 3 are the best.

In conjunction with Example 3 and Comparative Examples 1 and 2, it can be seen that the reaction conditions of Comparative Example 1 and Comparative Example 2 have exceeded the protection scope of the present application, and the prepared N-tert-butoxycarbonyl-4-dimethylaminopiper Pyridone yield and purity are all lower than Example 3, and PMI is higher than Example 3, which proves that the reaction conditions of Comparative Examples 1 and 2 are not suitable for the present application.

In conjunction with Example 3 and Comparative Examples 3 and 4, it can be seen that the ratio of the raw materials of Comparative Example 3 and Comparative Example 4 has exceeded the protection scope of the present application, and the prepared N-tert-butoxycarbonyl-4-dimethyl Aminopiperidone yield and purity are lower than that of Example 3, and PMI is higher than that of Example 3, which proves that the amount of reaction raw materials in Comparative Examples 3 and 4 is not suitable for this application.

This specific embodiment is only an explanation of this application, and it is not a limitation of this application. Those skilled in the art can make modifications to this embodiment without creative contribution according to needs after reading this specification, but as long as the rights of this application All claims are protected by patent law.

Claims (8)

1. a method for reductive amination N-tert-butoxycarbonyl-4-piperidone, is characterized in that, comprises the following steps: Step S1: mixing an organic solvent, N-tert-butoxycarbonyl-4-piperidone and dimethylamine methanol to obtain a raw material liquid; and loading the catalyst into a fixed hydrogenation bed; Step S2, pumping the raw material liquid into a fixed hydrogenation bed for reaction at a pressure of 2-2.5 MPa, a temperature of 50-100°C, a raw material flow rate of 0.1-1.6 L/min, and a hydrogen flow rate of 5-30 L/min to obtain a hydrogenated liquid; Step S3: concentrating the hydrogenation solution under reduced pressure until solids are precipitated to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone; Step S4: Mix the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone with ethanol, and heat and distill the ethanol to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidone, That is, the product of N-tert-butoxycarbonyl-4-piperidone reductive amination; the chemical equation of reductive amination N-tert-butoxycarbonyl-4-piperidone is as follows: A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone according to claim 1, wherein the raw material liquid comprises the following components by weight: 9.5-11.5 parts of organic solvent, 19-23 parts of N-tert-butoxycarbonyl-4-piperidone, 0.9-1 part of dimethylaminemethanol and 0.01-0.03 parts of catalyst. 2. the method for a kind of reductive amination N-tert-butoxycarbonyl-4-piperidone according to claim 1, is characterized in that, described catalyst is Pd/C, Pt/C, Rh/C, Ir /C, Ru/C or Os/C. 3. the method for a kind of reductive amination N-tert-butoxycarbonyl-4-piperidone according to claim 1, is characterized in that, described organic solvent is methanol, ethanol or Virahol. 4. a kind of method for reductive amination N-tert-butoxycarbonyl-4-piperidone according to claim 1, is characterized in that, in described step S1, organic solvent, N-tert-butoxycarbonyl- After mixing 4-piperidone and dimethylamine methanol, a step of filtering impurities is also included to finally obtain a raw material liquid. 5. A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone according to claim 1, characterized in that, in the step S3, the hydrogenation solution is kept at 50-60°C for less than Under the pressure of -70KPa, concentrate under reduced pressure until the solid precipitates to obtain the initially treated N-tert-butoxycarbonyl-4-dimethylaminopiperidone. 6. A method of reductive amination N-tert-butoxycarbonyl-4-piperidone according to claim 1, characterized in that, in said step S4, the initially treated N-tert-butoxycarbonyl-4 - The volume ratio of dimethylaminopiperidone to ethanol is 1: (9-11). 7. A method for reductive amination of N-tert-butoxycarbonyl-4-piperidone according to claim 1, characterized in that, in the step S4, the temperature for removing ethanol by heating is 50-60°C . 8. A N-tert-butoxycarbonyl-4-dimethylaminopiperidone, characterized in that, said N-tert-butoxycarbonyl-4-dimethylaminopiperidone is defined by any one of claims 1-8. prepared by the method described above.