Method for producing tetrahydropyrazine condensed ring derivative by using fixed bed

Abstract

The present disclosure relates to a method for producing tetrahydropyrazine fused ring derivatives using a fixed bed. The preparation process route is high in reaction speed, high in conversion rate, simple and safe to operate, low in cost and capable of being continuously carried out, and the impurity content can be controlled without complex post-treatment.

Description

Technical Field

[0001] The present disclosure relates to a method for producing tetrahydropyrazine fused-ring derivatives using a fixed bed. Background Art

[0002] Tetrahydropyrazine fused-ring derivatives are key fragments and synthetic intermediates of various drug molecules. For example, the dipeptidyl peptidase-IV (DPP-IV) inhibitor Sitagliptin Phosphate (III-B) developed by Merck & Co., Inc. was approved by the US FDA for marketing in October 2006 and is used to treat type 2 diabetes. Retagliptin Phosphate (III-A), which also has a tetrahydropyrazine fused-ring derivative fragment, has been declared for marketing, and the results show that it has excellent DPP-IV inhibitory effects.

[0003]

[0004] Regarding the preparation of tetrahydropyrazine fused-ring derivatives, there are many reports in the prior art. For example, WO2009082881A discloses the following preparation method:

[0005]

[0006] Using 2-cyanopyrazine as the starting material, 3-trifluoromethyl-imidazo[1,5-a]pyrazine is obtained through reduction, acylation, and intramolecular dehydration cyclization, and then the tetrahydropyrazine fused-ring intermediate is obtained through catalytic hydrogenation with hydrogen / palladium on carbon, which is subsequently used for the synthesis of retagliptin.

[0007] CN103724352A and CN106892926A disclose similar intermediate preparation methods:

[0008]

[0009] Methyl 2-amino-2-pyrazine-acetate is subjected to TFFA acylation and dehydration cyclization to obtain an imidazopyrazine intermediate, and this intermediate is subjected to catalytic hydrogenation with hydrogen / palladium on carbon to obtain a tetrahydropyrazine fused-ring derivative.

[0010] CN114478536A discloses that the imidazopyrazine intermediate is subjected to catalytic hydrogenation with hydrogen / palladium on carbon under alkaline conditions to obtain a tetrahydropyrazine fused-ring derivative.

[0011] Looking at the above synthetic methods, all of them use 10% Pd / C as the catalyst and carry out the reaction in a special high-pressure hydrogenation reactor, and certain post-treatment is required to obtain the target product that meets the requirements. When the above methods are used in the industrial preparation of tetrahydropyrazine fused-ring derivatives, there are problems such as long reaction time, high cost, high safety risk of the high-pressure reactor, complex post-treatment, and excessive impurity content. Therefore, there is an urgent need for a method for the industrial preparation of tetrahydropyrazine fused-ring derivatives with low cost, high yield, good purity, qualified impurity content, high safety, and simple post-treatment.

[0012] A fixed-bed reactor is a reactor applied to high-pressure gas-liquid-solid three-phase reactions. The reactor is filled with granular solid catalysts, and the solid particles remain stationary. While the gas and liquid materials flow through the gaps between the particles and pass through the stationary fixed-bed layer, a heterogeneous reaction process is achieved. CN112724187A discloses a method for preparing an obeticholic acid intermediate using fixed-bed catalytic hydrogenation, and CN112574091A discloses a method for preparing bazedoxifene using fixed-bed catalytic hydrogenation. Summary of the Invention

[0013] In order to overcome the deficiencies of the prior art, the purpose of the present disclosure is to provide a new method for preparing a tetrahydropyrazine fused-ring derivative represented by Formula II.

[0014] The present disclosure provides a method for preparing a compound represented by Formula II, comprising: reacting the compound represented by Formula I with hydrogen in a fixed-bed reactor filled with a catalyst.

[0015]

[0016] The present disclosure provides a method for preparing a compound represented by Formula II, including the following steps:

[0017] (1) Loading the catalyst into a fixed-bed reactor;

[0018] (2) Dissolving the compound represented by Formula I in an organic solvent, and then simultaneously transporting the solution of the compound represented by Formula I and hydrogen to a mixer for mixing to obtain a mixed material;

[0019] (3) Transporting the mixed material to a fixed-bed reactor loaded with a catalyst for a hydrogenation reaction.

[0020] In some embodiments, the catalyst is selected from palladium / carbon, palladium / aluminum oxide, palladium hydroxide / aluminum oxide, platinum / carbon, platinum / aluminum oxide, or ruthenium / carbon.

[0021] In some embodiments, the catalyst is selected from palladium hydroxide / aluminum oxide.

[0022] In some embodiments, the content of the catalyst is selected from 0.1 - 10% w / w, preferably 0.5 - 5% w / w, and specifically can be 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0% or a value between any two of these values.

[0023] In some embodiments, in step (3), the temperature of the hydrogenation reaction is selected from 10 - 80°C, preferably 30 - 50°C, and specifically can be selected from 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C or a value between any two of these values.

[0024] In some embodiments, in step (2), the flow rate of the compound solution represented by formula I is 0.002 - 0.2 CV / min, preferably 0.02 - 0.2 CV / min, and specifically can be selected from 0.02 CV / min, 0.04 CV / min, 0.06 CV / min, 0.08 CV / min, 0.10 CV / min, 0.12 CV / min, 0.14 CV / min, 0.16 CV / min, 0.18 CV / min, 0.2 CV / min or a value between any two of these values. Here, CV / min represents the column volume flowing through per minute. For example, when the flow rate is 0.2 CV / min and the volume of the fixed bed is 5 mL, the flow rate of the compound solution represented by formula I is 1.0 mL / min.

[0025] In some embodiments, in step (2), the flow rate of hydrogen is 10 - 100 times the flow rate of the compound solution represented by formula I.

[0026] In some embodiments, in step (2), the input pressure of hydrogen is 2 - 5 Mpa, and specifically can be selected from 2 MPa, 3 MPa, 4 MPa, 5 MPa or a value between any two of these values.

[0027] In some embodiments, in step (2), the concentration of the compound solution represented by formula I is selected from 0.01 - 1 M, preferably 0.05 - 0.5 M, and specifically can be 0.05 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M or a value between any two of these values.

[0028] In some embodiments, the organic solvent is selected from one or more of tetrahydrofuran, ethyl acetate, ethanol, and methanol, preferably tetrahydrofuran.

[0029] In some embodiments, the method for preparing the compound shown in Formula II described in the present disclosure further includes the steps of continuously distilling, crystallizing, and filtering the reaction solution flowing out of the fixed-bed reactor.

[0030] The present disclosure also provides a method for preparing the compound shown in Formula III, which includes reacting the compound of Formula II prepared by the aforementioned method with the compound of Formula V to form the compound of Formula VI, and then removing the protecting group to obtain the compound of Formula III:

[0031]

[0032] By using a fixed-bed reactor, the present disclosure has screened out advantageous reaction conditions, improved the original hydrogenation process. Compared with the traditional reaction kettle process, its beneficial effects are as follows: 1) The reactor volume is reduced by 100 times, greatly reducing the gas-liquid holdup and achieving inherent safety; 2) The process is simplified, the conversion rate is increased, and the content of impurities can be effectively controlled without post-treatment; 3) The reduction of the palladium content in the catalyst improves safety and also reduces the production cost. Description of the Drawings

[0033] Figure 1 . Schematic diagram of the reaction of the fixed-bed reactor. Detailed Description of the Embodiments

[0034] The following will explain the present disclosure in more detail in combination with the examples. The examples of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and the essence and scope of the present disclosure are not limited thereto.

[0035] The content of the impurities or substances described in the present disclosure can be obtained by HPLC detection.

[0036] HPLC method (General Rules 0512, Volume IV, Chinese Pharmacopoeia 2015 Edition) detection conditions: chromatographic column (Waters SunFireTMC18, specification: 4.6 mm × 150 mm, 3.5 μm), eluting with diammonium hydrogen phosphate solution and acetonitrile solution as the mobile phase. Among them, the system suitability solution, the test solution, and the 1% control solution are respectively determined, and the percentage content of impurities is calculated according to the following formula:

[0037]

[0038] Among them, the relative retention time of the dimer impurity is 26.261 min, and the solvent addition impurity is 13.046 min.

[0039] Example 1

[0040]

[0041] As Figure 1The fixed-bed reactor shown in the figure was used. 3 g of 0.5% w / w Pd(OH)2 / Al2O3 was loaded into a 5 mL fixed-bed reaction tube. 1 g of the compound of Formula I (prepared according to the method disclosed in CN114478536A) was dissolved in 30 mL of tetrahydrofuran. The flow rate, pressure, temperature and other parameters were set according to Table 1, and the compound of Formula II was continuously prepared through the fixed-bed reactor. The impurity content is shown in Table 1.

[0042] Table 1 Optimization of reaction conditions

[0043]

[0044] The results showed that increasing the temperature, decreasing the pressure and too high raw material flow rate would all lead to an increase in impurity content, and the gas flow rate had little effect on the impurity level.

[0045] Example 2

[0046]

[0047] 1) Add 134 kg of tetrahydrofuran to a 200 L dissolution tank, start stirring, and add 5.0 kg of the compound shown in Formula I (prepared according to the method disclosed in CN114478536A) to the dissolution tank, and the materials are dissolved;

[0048] 2) Add 0.9 kg of 0.5% Pd(OH)2 / Al2O3 to a 1.5 L fixed-bed reaction tube;

[0049] 3) Start the machine, enter the interface of the hydrogenator, open the nitrogen flow meter, purge and replace the air with nitrogen, and then purge with hydrogen. Open the back pressure valve to a back pressure of 4 MPa;

[0050] 4) Set the liquid flow rate to 132 mL / min, the gas flow rate to 3.6 slm, and the temperature to 30 °C, and then start the infusion pump and the gas flow meter for the hydrogenation reaction;

[0051] 5) After the impurity level of the material meets the requirements, connect to the continuous distillation, crystallization and filtration processes, collect the material, and the yield of the obtained compound of Formula II is 95%, the purity is 99.7%, and the impurity content is 0.3%.

[0052] Comparative example

[0053]

[0054] 1) Add 30 mL of tetrahydrofuran to a 50 mL single-necked flask, stir magnetically, and add 1 g of the compound shown in Formula I (prepared according to the method disclosed in CN114478536A) to the single-necked flask;

[0055] 2) Add 0.1 g of 0.5% Pd(OH)2 / Al2O3 into a single-necked flask, place the single-necked flask in an autoclave, and react for 18 hours under the conditions of controlling the external temperature at about 40 °C and the hydrogen pressure at about 4 MPa;

[0056] 3) After the reaction, the sampling test results show that the proportion of the compound shown in Formula I is 80.4%, the proportion of the compound shown in Formula II is 16.7%, and the impurity content is 2.9%. The yield is calculated to be 14% by the external standard method.

Claims

1. A method for preparing a compound of formula II, comprising: The compound represented by formula I is reacted with hydrogen in a fixed bed reactor filled with a catalyst, 2. The method according to claim 1, comprising the steps of: (1) loading the catalyst into a fixed bed reactor; (2) dissolving the compound represented by formula I in an organic solvent, and then conveying the solution of the compound represented by formula I and hydrogen to a mixer for mixing to obtain a mixed material; (3) The mixed material is transported to a fixed bed reactor loaded with a catalyst for hydrogenation reaction.

3. The method according to claim 1 or 2, wherein the catalyst is selected from palladium / carbon, palladium / aluminum oxide, palladium hydroxide / aluminum oxide, platinum / carbon, platinum / aluminum oxide or ruthenium / carbon, preferably palladium hydroxide / aluminum oxide.

4. The method according to claim 3, wherein the content of the catalyst is selected from 0.1-10% w / w, preferably 0.1-5% w / w.

5. The method according to any one of claims 2 to 4, wherein in step (3), the temperature of the hydrogenation reaction is selected from 10-80°C, preferably 30-50°C.

6. The method according to any one of claims 2 to 5, wherein in step (2), the flow rate of the solution of the compound represented by formula I is 0.002 to 0.2 CV / min, preferably 0.02 to 0.2 CV / min.

7. The method according to any one of claims 2 to 5, wherein in step (2), the flow rate of hydrogen is 10 to 100 times the flow rate of the solution of the compound represented by formula I.

8. The method according to any one of claims 2 to 6, wherein in step (2), the input pressure of hydrogen is 2 to 5 MPa, preferably 4 MPa.

9. The method according to any one of claims 2 to 7, wherein the organic solvent is selected from one or more of tetrahydrofuran, ethyl acetate, ethanol and methanol, preferably tetrahydrofuran.

10. A method for preparing a compound of formula III, comprising the steps of reacting a compound of formula II prepared according to the method of any one of claims 1 to 8 with a compound of formula V to produce a compound of formula VI, and then removing the protecting group to obtain a compound of formula III:

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