CN115368296A - Preparation method of N-tert-butyloxycarbonyl-4-aminopiperidine - Google Patents

Abstract

The invention discloses a preparation method of N-tert-butyloxycarbonyl-4-aminopiperidine in the technical field of drug intermediate synthesis, aiming at solving the problems that the synthesis and preparation of N-tert-butyloxycarbonyl-4-aminopiperidine in the prior art usually requires severer reaction conditions, has high requirements on reaction equipment, generates more byproducts in the preparation process and the like, and the preparation method comprises the following steps of adding N-tert-butyloxycarbonyl-4-oxime piperidine into an organic solvent, keeping a certain temperature, and adding Raney nickel in a nitrogen atmosphere; replacing the gas system with hydrogen, replacing the gas system with nitrogen again after a certain reaction time, performing filter pressing, and performing reduced pressure concentration on the filtrate to obtain the N-tert-butyloxycarbonyl-4-aminopiperidine. The preparation method provided by the invention has the advantages of safe preparation process, mild reaction conditions and improved product purity.

Description

A kind of preparation method of N-tert-butoxycarbonyl-4-aminopiperidine

technical field

The invention relates to a preparation method of N-tert-butoxycarbonyl-4-aminopiperidine, belonging to the technical field of pharmaceutical intermediate synthesis.

Background technique

N-tert-butoxycarbonyl-4-aminopiperidine is widely used as an important chemical or pharmaceutical intermediate, such as relebactam, which is widely used in the synthesis of active drug molecules for the treatment of various diseases and has attracted wide attention. This is a diazabicyclooctane inhibitor with broad-spectrum anti-β-lactamase activity, including class A (extended-spectrum β-lactamase and KPC) and class C (AmpC enzyme).

However, at present, the synthesis and preparation of N-tert-butoxycarbonyl-4-aminopiperidine usually requires relatively harsh reaction conditions, and the requirements for reaction equipment are also very high. Many by-products will be produced during the preparation process, which will affect the final preparation. The purity of the N-tert-butoxycarbonyl-4-aminopiperidine obtained.

Contents of the invention

The object of the present invention is to overcome the deficiencies in the prior art, and provide a preparation method of N-tert-butoxycarbonyl-4-aminopiperidine, which has a safe preparation process, mild reaction conditions, and improved product purity.

In order to achieve the above object, the present invention is achieved by adopting the following technical solutions:

According to the first aspect of the invention, a kind of preparation method of N-tert-butoxycarbonyl-4-aminopiperidine comprises the following steps, adding N-tert-butoxycarbonyl-4-oxime piperidine in organic solvent, keeping temperature 1 , add Raney nickel under a nitrogen atmosphere; replace the gas system with hydrogen, stir, and after the reaction time II, replace the gas system with nitrogen again, press filter, take the filtrate and concentrate under reduced pressure to obtain N-tert-butoxycarbonyl -4-aminopiperidine.

Further, the organic solvent is one or more of methanol, ethanol, isopropanol or n-propanol.

Further, the volume-to-mass ratio of the organic solvent to N-tert-butoxycarbonyl-4-oxime piperidine is 3-6:1 mL/g.

Further, the temperature I ranges from 25 to 30°C.

Further, the mass ratio of Raney nickel to N-tert-butoxycarbonyl-4-oxime piperidine is 1:5-10.

Further, the pressure range of the gas system is 20-22 atmospheres.

Further, the reaction time II is 16-20 hours.

Further, the Raney nickel has a wide range of models, including TLD-A-I, TLD-A-II, TLD-A-III, TLD-B-I, TLD-B-II, TLD-B- Ⅲ, TLD-C-Ⅰ, TLD-C-Ⅱ and TLD-C-Ⅲ.

According to the second aspect of the invention, there is also provided N-tert-butoxycarbonyl-4-aminopiperidine, which is prepared by any one of the above-mentioned preparation methods.

Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

The intermediate drug N-tert-butoxycarbonyl-4-oxime piperidine of the present invention can be prepared by N-tert-butoxycarbonyl-4-ketopiperidine, only one step is needed, and the reaction conditions are safe in the whole preparation process, and no Ultra-high temperature and ultra-low temperature reaction conditions;

The preparation raw materials are simple and easy to obtain, and there is no raw material drug that needs to be filed; the preparation cost is low, and no large-scale equipment or specific customized equipment is required; the preparation process is relatively safe, and there are no toxic and harmful by-products, and there are no high-toxicity and high-boiling intermediates Body produced;

Moreover, the chemical purity of N-tert-butoxycarbonyl-4-aminopiperidine obtained by the preparation method of the present invention is as high as 99%, and the yield is as high as 95%.

Description of drawings

1 is a schematic diagram of the GC spectrum of N-tert-butoxycarbonyl-4-aminopiperidine prepared in Example 1 of the present invention;

2 is a schematic diagram of the ¹ H NMR spectrum of N-tert-butoxycarbonyl-4-aminopiperidine prepared in Example 1 of the present invention;

Fig. 3 is a schematic diagram of the ¹³ C NMR spectrum of N-tert-butoxycarbonyl-4-aminopiperidine prepared in Example 1 of the present invention.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings. The following examples are only used to illustrate the technical solution of the present invention more clearly, but not to limit the protection scope of the present invention.

Neither the endpoints nor any values of the ranges disclosed herein are limited to this precise range or value, and these ranges or values are understood to include values approaching these ranges or values. For numerical ranges, between the endpoints of each range, between the endpoints of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, these values Ranges should be considered as specifically disclosed herein.

For the purposes of this specification and the appended claims, unless otherwise stated, all figures expressing amounts, percentages or ratios and other numerical values used in this specification and the appended claims are understood to be in all cases Modified by the term "about". Furthermore, all ranges disclosed herein are inclusive of endpoints and independently combinable.

Example 1:

In a 500 mL autoclave, first add 200 mL of methanol, and then add N-tert-butoxycarbonyl-4-oxime piperidine (40 g). Passivate the reactor with nitrogen gas. Add 8 grams of Raney nickel TLD-A-I to the system. Cover the kettle lid, replace the system in the kettle with hydrogen, raise the pressure to 20 atmospheres, and keep stirring the reaction solution for 16 hours while maintaining 20-25°C.

After the reaction was completed, press filter, rinse the filter cake with 60 mL of methanol, and concentrate the filtrate under reduced pressure to obtain 34.2 g of N-tert-butoxycarbonyl-4-aminopiperidine with a yield of 95%.

Example 2:

In a 10L autoclave, first add 5L of methanol, and then add N-tert-butoxycarbonyl-4-oxime piperidine (1kg). Passivate the reactor with nitrogen gas. Add 200 grams of Raney nickel TLD-A-I to the system. Cover the kettle lid, replace the system in the kettle with hydrogen, raise the pressure to 20 atmospheres, and keep stirring the reaction solution for 16 hours while maintaining 20-25°C.

After the reaction was completed, press filter, rinse the filter cake with 1.5 L of methanol, and concentrate the filtrate under reduced pressure to obtain 872 g of N-tert-butoxycarbonyl-4-aminopiperidine with a yield of 96%.

Example 3:

In a 20L autoclave, first add 10L of methanol, and then add N-tert-butoxycarbonyl-4-oxime piperidine (2kg). Passivate the reactor with nitrogen gas. Add 400 grams of Raney nickel TLD-A-I to the system. Cover the kettle lid, replace the system in the kettle with hydrogen, raise the pressure to 20 atmospheres, and keep stirring the reaction solution for 16 hours while maintaining 20-25°C.

After the reaction was completed, press filter, rinse the filter cake with 3 L of methanol, and concentrate the filtrate under reduced pressure to obtain 1780 g of N-tert-butoxycarbonyl-4-aminopiperidine with a yield of 98%.

The properties of the products prepared in the examples of the present invention will be analyzed below in conjunction with the accompanying drawings.

The present invention prepares N-tert-butoxycarbonyl-4-aminopiperidine by N-tert-butoxycarbonyl-4-oxime piperidine, and the reaction formula of the process is as follows:

The obtained N-tert-butoxycarbonyl-4-aminopiperidine was analyzed by gas chromatography.

The gas chromatography analysis conditions are shown in Table 1, and the injection volume is 5.000 μL.

Table 1: N-tert-butoxycarbonyl-4-aminopiperidine gas chromatography analysis parameters

In conjunction with Figure 1, the test results include one main gas chromatographic peak, and the specific gas chromatographic analysis parameters are shown in Table 2:

Table 2: N-tert-butoxycarbonyl-4-aminopiperidine gas chromatography analysis parameters

Next, NMR analysis was performed on the prepared N-tert-butoxycarbonyl-4-aminopiperidine, and the NMR analysis conditions were: test frequency: 400 MHz; solvent: deuterated methanol CD ₃ OD.

In conjunction with Fig. 2 and Fig. 3, it can be judged that the structural formula of the N-tert-butoxycarbonyl-4-aminopiperidine made is

The above is only a preferred embodiment of the present invention, it should be pointed out that for those of ordinary skill in the art, without departing from the technical principle of the present invention, some improvements and modifications can also be made. It should also be regarded as the protection scope of the present invention.

Claims (8)

1. A preparation method of N-tert-butyloxycarbonyl-4-aminopiperidine is characterized by comprising the following steps: comprises the following steps of (a) carrying out,

adding N-tert-butyloxycarbonyl-4-oxime piperidine into an organic solvent, keeping the temperature I, and adding raney nickel under the nitrogen atmosphere; and then replacing the gas system with hydrogen, stirring, reacting for II, replacing the gas system with nitrogen again, performing filter pressing, and performing reduced pressure concentration on the filtrate to obtain the N-tert-butoxycarbonyl-4-aminopiperidine.

2. The process according to claim 1, wherein the reaction mixture is N-t-butoxycarbonyl-4-aminopiperidine: the organic solvent is one or more of methanol, ethanol, isopropanol or n-propanol.

3. The process according to claim 2, wherein the reaction mixture is N-t-butoxycarbonyl-4-aminopiperidine: the volume mass ratio of the organic solvent to the N-tert-butoxycarbonyl-4-oxime piperidine is 3-6.

4. The process according to claim 1, wherein the reaction mixture is N-t-butoxycarbonyl-4-aminopiperidine: the temperature I range is 25-30 ℃.

5. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the mass ratio of the raney nickel to the N-tert-butoxycarbonyl-4-oxime piperidine is 1.

6. The process according to claim 1, wherein the reaction mixture is N-t-butoxycarbonyl-4-aminopiperidine: the pressure range of the gas system is 20-22 atmospheric pressures.

7. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the reaction time II is 16-20 h.

8. An N-tert-butoxycarbonyl-4-aminopiperidine characterized by: prepared by the preparation method of any one of claims 1 to 7.

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