Preparation method of gemigliptin intermediate compound

Abstract

The invention relates to a preparation method of a gemigliptin intermediate compound, and particularly relates to a preparation method of a gemigliptin intermediate compound as shown in a formula 1, namely (S)-4-amino-3-((t-butyloxycarboryl) amino) tert-butyl butyrate, which is prepared by taking t-butyloxycarboryl-L-aspartic acid-4-tert-butyl ester as a starting raw material and carrying out three-step chemical reaction. The method has the advantages of cheap and easily available starting materials, simple and controllable operation, high reaction yield, easy separation of intermediates in each step, high purity, and suitableness for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and specifically, it provides a method for preparing a gilgliptin intermediate compound. Background Technology

[0002] Giglitazone (CAS No.: 911637-19-9) is a dipeptidyl peptidase-4 (DPP-4) inhibitor with the following structural formula: The drug works by mimicking the body's naturally produced incretin hormones to stimulate insulin release, thereby responding to food intake and improving blood sugar control. Clinically, it is mainly used for the treatment of type 2 diabetes.

[0003] The method for preparing intermediate compound (2) of the drug gilagliptin using compound of formula 1 as an intermediate has been reported in CN103080088B and WO2006 / 104356. The synthetic route is as follows: Currently, there are few reported synthetic routes for the preparation of compounds of formula 1, which can be roughly summarized into three categories: Synthetic route 1: via an azide intermediate, as shown in the following formula: This method uses (3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-pentanoic acid as the starting material, and proceeds through tert-butyl esterification, reduction, hydroxyl activation, azidation, and reduction steps to obtain the compound of formula 1. The main drawbacks of this route are: 1) the reaction route is relatively long, involving five steps; 2) the third step uses highly toxic methanesulfonyl chloride; and 3) the fourth step uses explosive sodium azide. The entire route is costly and carries high safety risks, is unfriendly to humans and the environment, and is unsuitable for industrial production.

[0004] Synthetic route 2: Synthesized via benzylamine intermediate, the synthetic route is shown in the following formula: This method uses tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester as the starting material, and proceeds sequentially through carboxylic acid esterification to amide compound, reduction, and hydrogenation debenzylation to obtain compound 1. The main drawbacks of this route are: 1) the reported yields for each step are low; 2) each intermediate requires column chromatography purification; and 3) two of the three steps involve the use of noble metal (ruthenium and palladium) catalysts, resulting in high costs. Therefore, this route is not suitable for industrial production.

[0005] Synthetic route 3: A synthetic method for catalytic hydrogenation is reported, as shown in the following formula: This method uses tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester as the starting material, and obtains the compound of formula 1 through amination, dehydration, and hydrogenation reduction. The synthesis steps of this method are relatively short, but the disadvantages are also obvious. The main drawbacks of the third step catalytic hydrogenation include: a) the use of expensive palladium hydroxide catalyst; b) the use of acetic acid as solvent, which is highly corrosive to the equipment and has special requirements for the catalytic hydrogenation equipment, requiring acid resistance, limiting production capacity, and resulting in high equipment costs; at the same time, the acetic acid concentration is 20 times, and the post-processing requires concentration of acetic acid, which consumes a lot of energy, affects the health of operators, poses safety hazards for scale-up, and is not conducive to industrial production; c) according to the literature (provide the reference number), the yield of this route can reach 70-80%. However, when the applicant repeated the process, he found that the reaction yield was only 40-50% at a scale of 200g, and the process repeatability was poor. The inventor verified the method through multiple batch experiments (200g batch) and found that the reaction yield could only reach 40-50%, while the yield reported in the literature was 70-80%. The process is unstable and has poor repeatability.

[0006] Therefore, it is of great significance to develop a simple, high-yield, low-cost, and industrially suitable method for preparing tert-butyl (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate. Summary of the Invention

[0007] The objective of this invention is to provide a method for preparing (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate tert-butyl ester (i.e., compound of formula 1) that is simple to operate, has a high product yield, does not use toxic and expensive reagents, is low in cost, and is suitable for industrial production.

[0008] A first aspect of the present invention provides a method for preparing a compound of formula 1, characterized by comprising the steps of: (i) In the presence of an organic base, tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester is reacted with a nitrogen source to obtain compound a; (ii) The compound of formula a is reacted with cyanuric chloride to obtain the compound of formula b; (iii) The compound of formula b is reacted with a hydrogen source to obtain the compound of formula 1.

[0009] In another preferred embodiment, in step (iii), the hydrogen source is selected from the group consisting of borane tetrahydrofuran, borane dimethyl sulfide, or combinations thereof.

[0010] In another preferred embodiment, step (iii) is carried out in an organic solvent, preferably selected from the group consisting of tetrahydrofuran, dichloromethane, or combinations thereof.

[0011] In another preferred embodiment, in step (iii), the mass ratio of the raw material compound b to the organic solvent is 1:(5-6).

[0012] In another preferred embodiment, in step (iii), the molar ratio of the hydrogen source to the starting compound of formula b is (2-5):1.

[0013] In another preferred embodiment, in step (iii), the reaction is carried out at 0-35°C.

[0014] In another preferred embodiment, in step (iii), the reaction time is 1-7 hours.

[0015] In another preferred embodiment, step (iii) includes: 1) A solution containing compound b is reacted with a hydrogen source to obtain a reaction mixture; 2) The reaction mixture is post-treated to obtain pharmaceutical intermediate compound of formula 1.

[0016] In another preferred embodiment, the post-processing includes the steps of: separating the reaction mixture, alkalizing the aqueous phase, extracting with methyl tert-butyl ether, concentrating under reduced pressure, slurrying with n-heptane, filtering and drying to obtain the product.

[0017] In another preferred embodiment, the reaction steps are as follows: reacting the tetrahydrofuran solvent of compound b with a borane tetrahydrofuran solution, quenching the reaction, concentrating to remove the solvent, adding DCM, cooling, and acidifying with hydrochloric acid.

[0018] In another preferred embodiment, after the reaction is completed, the post-processing steps include: separating the reaction product, alkalizing the aqueous phase with ammonia, extracting with methyl tert-butyl ether, concentrating the organic phase and adding n-heptane to slurry, filtering and drying to obtain the product.

[0019] In another preferred embodiment, in step (i), the nitrogen source is selected from the group consisting of ammonia, ammonium bicarbonate, or a combination thereof.

[0020] In another preferred embodiment, in step (iii), the mass ratio of the raw material compound b to the solvent is 1:(4~8).

[0021] In another preferred embodiment, in step (i), the organic base is pyridine.

[0022] In another preferred embodiment, the reaction is carried out in the presence of an activator; preferably, the activator is selected from the group consisting of Boc anhydride, ethyl chloroformate, or combinations thereof.

[0023] In another preferred embodiment, in step (i), the reaction is carried out in an organic solvent; preferably, the solvent is selected from the group consisting of pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

[0024] In another preferred embodiment, in step (i), the molar ratio of the raw material tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester to the nitrogen source is 1:(1-1.5).

[0025] In another preferred embodiment, in step (ii), the reaction is carried out in an organic solvent; preferably, the organic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

[0026] In another preferred embodiment, in step (ii), the molar ratio of the raw material compound of formula a to cyanuric chloride is 1:(0.5~1.5).

[0027] A second aspect of the present invention provides a method for preparing a compound of formula 1, comprising the following steps: The compound of formula b was reacted with boranetetrahydrofuran to obtain the compound of formula 1.

[0028] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0029] The inventors have developed a novel method for preparing the pharmaceutical intermediate (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate tert-butyl ester (compound of formula 1). Based on previously reported methods, this method innovates the crystallization process of the intermediate in the earlier steps, focusing on the reduction of the cyano group to the amino group. It eliminates the use of precious palladium catalysts in the original route and removes the need for high-pressure hydrogenation in an acidic environment, thus freeing up equipment limitations. This invention utilizes inexpensive and readily available raw materials, is simple and controllable to operate, yields high output, and produces high-purity products, making it suitable for large-scale industrial production.

[0030] The purpose of this invention is to provide a method for preparing (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate tert-butyl ester (i.e., compound of formula 1), a pharmaceutical intermediate suitable for industrial production. This method includes the following steps: The starting material compound b is dissolved in a solvent, a compound with a hydrogen source is added, and the reaction is carried out at a certain temperature. After the reaction is completed, water is added to quench the reaction, and the compound of formula 1 is obtained after post-treatment. The starting material intermediates, compounds of formula a and b, are prepared according to the method in the literature (CN103080088A).

[0031] In another preferred embodiment, in the preparation method, the solvent is selected from tetrahydrofuran and dichloromethane, preferably tetrahydrofuran.

[0032] In another preferred embodiment, in the preparation method, the mass ratio of the raw material compound b to the solvent is 1:(4-8), preferably 1:5.

[0033] In another preferred embodiment, the hydrogen source in the preparation method is selected from borane tetrahydrofuran, borane dimethyl sulfide, and preferably borane tetrahydrofuran.

[0034] In another preferred embodiment, in the preparation method, the molar ratio of the hydrogen source borane tetrahydrofuran to the raw material compound b is (2-5):1, preferably 3:1.

[0035] In another preferred embodiment, the reaction time in the preparation method is 1-7 hours, preferably 3-4 hours.

[0036] In another preferred embodiment, the specific temperature in the preparation method is 0-35℃, preferably 0-5℃.

[0037] Compared with the prior art, the preparation method of the present invention has the following advantages: (1) Significantly reduced core raw material costs and superior process economy. This invention completely eliminates the expensive palladium / palladium catalysts relied upon in traditional processes, instead using inexpensive and readily available borane complexes as the key reducing agent. Simultaneously, through full-route optimization, each intermediate and final product can be efficiently purified through a simple "slurrying" operation, completely avoiding the complex, time-consuming, and difficult-to-scale deep purification methods such as column chromatography and multiple recrystallization required in the background technology. These two improvements significantly reduce material and purification costs from the source, providing a key economic advantage for large-scale production.

[0038] (2) The reaction conditions are mild and safe, and the equipment and operation requirements are simplified. Compared with the harsh conditions of high-pressure catalytic hydrogenation in a highly corrosive medium required by traditional processes, this invention adopts a borane reduction system at atmospheric pressure and low temperature. This innovation not only eliminates the dependence on special corrosion-resistant high-pressure equipment, allowing production to be carried out using conventional equipment, thus reducing the investment and maintenance threshold, but also greatly improves the safety (avoiding the use of hydrogen and strong acids) and operability of the process. The reaction time is shortened, and the post-processing is simplified, which better meets the core requirements of industrial production for safety, efficiency and stability.

[0039] (3) The product yield and purity are stable and excellent, and the process reproducibility and reliability are strong. This invention adopts a highly selective borane reduction system (see Comparative Example 4) and synergistically optimizes the reaction conditions of each step, thereby effectively controlling the quality of the intermediates. As a result, a high yield (approximately 80%) and high purity (>98%) of the final product can be achieved with only simple pulping and purification. This result is stable and reliable, successfully solving the problems of low yield (approximately 40%) and poor reproducibility caused by impurity accumulation in the existing technical route (Comparative Example 1). The combination of simplified purification method and stable high-quality output ensures the overall robustness and scale-up feasibility of the process.

[0040] In summary, this invention is not a simple replacement of the purification steps, but rather, through innovative changes to key reaction steps and refined control of the entire pathway, it creatively adapts the target molecule to an industrially friendly and simple purification method. This process achieves synergistic improvements in cost, safety, efficiency, and quality controllability, providing a practical and advantageous industrial production route for key intermediates of gitagliptin.

[0041] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0042] Example 1 The purpose of this embodiment is to provide a method for preparing a gilgliptin intermediate compound, the structural formula of which is shown in Formula 1: Formula 1 The preparation of compound 1 includes the following steps: Step (i): Preparation of compound a (compound a) 900 g of starting material tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester (3.11 mol) and 2.7 kg of dimethylformamide were added to a reaction flask and stirred at 20-30 °C to dissolve. Then, 883 g of Boc anhydride (4.05 mol) and 310 g of ammonium bicarbonate (3.92 mol) were added, followed by dropwise addition of 153 g of pyridine (1.93 mol). The reaction was allowed to proceed for 3-4 h. After the reaction was confirmed to be complete by HPLC, 3.6 kg of water and 4.5 kg of methyl tert-butyl ether were added. The mixture was stirred and extracted for 30 min, and then separated. The aqueous phase was back-extracted with 1.8 kg of methyl tert-butyl ether, and the organic phases were combined. The organic phase was then washed twice with 2.7 kg of sodium chloride solution. The methyl tert-butyl ether in the resulting organic phase was concentrated under reduced pressure and then 2.7 kg of n-heptane was added for slurrying. The slurrying temperature was 0-5 °C, the stirring speed was 200-300 rpm, and the slurrying time was 30 min. The content of the target product in the mother liquor was ≤0.5% by HPLC. The mixture was then filtered and dried to obtain 852 g of white to off-white solid title compound (2.95 mol), with a yield of 94.9%, HPLC purity of 95.5%, and melting point of 76.5-77.6 °C.

[0043] Step (ii): Preparation of compound b 358 g of compound a (1.24 mol) and 1.0 kg of dimethylformamide were added to a reaction flask. After stirring and dissolving, the mixture was cooled to 0-5 °C, and 290 g of cyanuric chloride (1.57 mol) was added. The mixture was then heated to 20-30 °C and reacted for 3-4 h. After the reaction was complete as determined by HPLC, 1800 g of 1% NaOH solution and 1800 g of methyl tert-butyl ether were added. The pH of the solution was adjusted to 8-10 with 10% NaOH, and the mixture was stirred and extracted for 30 min. The mixture was separated, and the aqueous phase was back-extracted once with 720 g of methyl tert-butyl ether. The organic phases were then combined. The mixture was washed twice with 360 g of 1% NaOH solution and twice with 360 g of 10% NaCl solution. The organic phase was concentrated under reduced pressure to obtain methyl tert-butyl ether, and then 1.074 kg of n-heptane was added for slurrying. The slurrying temperature was 0-5 °C, the stirring speed was 200-300 rpm, and the slurrying time was 30 min. The content of the target product in the mother liquor was ≤0.5% as determined by HPLC. The compound was then filtered and dried to obtain 319 g of a white solid (1.18 mol) of the title compound, with a yield of 95.2%, an HPLC purity of 95.4%, and a melting point of 79.4-79.7 °C.

[0044] Using nuclear magnetic resonance hydrogen spectroscopy ( 1 The structure was characterized by H NMR. 1 The H NMR data are as follows: 1H NMR (400MHz, (CD3)2SO), δ 1.41 (s, 18H), 2.73~2.85 (m, 2H), 4.66 (q, J=8Hz, 1H), 7.78 (d, J=8Hz, 1H). Step (iii): Preparation of compound 1 (compound 1, namely (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate tert-butyl ester) 270 g of compound b (1.0 mol) and 1.35 kg of tetrahydrofuran were added to a reaction flask. After stirring and dissolving, the mixture was cooled to 0-5 °C, and 3000 ml of borane tetrahydrofuran solution (concentration 1.0 mol / L, containing 3.0 mol of borane) was added dropwise under controlled temperature, and the reaction was allowed to proceed for 3-4 h. After the reaction of the starting material was confirmed to be complete by HPLC, 270 g of water was added to quench the reaction, and then the tetrahydrofuran was removed by concentration. 540 g of DCM was added to the residue, the temperature was lowered to 0-5 °C, and then acidified with 1N hydrochloric acid. The mixture was separated, and the aqueous phase was alkalized with ammonia. Then, 1080 g of methyl tert-butyl ether was added for extraction. The obtained organic phase was concentrated with methyl tert-butyl ether under reduced pressure, and then 1.074 kg of n-heptane was added for slurrying. The slurrying temperature was 0-5 °C, the stirring speed was 200-300 rpm, and the slurrying time was 30 min. The mother liquor showed almost no target product. The product was then filtered and dried to obtain 220 g of a white solid (0.80 mol) of the title compound, with a yield of 80.3%, HPLC purity of 98.2%, and melting point of 86.8-87.7 °C. The obtained product was analyzed by NMR, and the experimental results are as follows: 1 H NMR (400MHz, (CD3)2SO), δ 1.37 (s, 9H), 1.38 (s, 9H), 2.17 (dd, J=8Hz, 16Hz, 1H), 2.48 (dd, J=8Hz, 16Hz, 1H), 2.48 (m, 2H), 3.67 (br s, 1H), 6.63 (d, J=8Hz, 1H). The target compound described in the title has been confirmed.

[0045] In the above method, no deep purification such as column chromatography or multiple recrystallization is required between each step. A good yield can be obtained simply by using solvents such as n-heptane to pulp the products of each step, which is suitable for large-scale production.

[0046] Example 2 The purpose of this embodiment is to provide a method for preparing a gilgliptin intermediate compound, the structural formula of which is shown in Formula 1: Formula 1 The preparation of compound 1 includes steps (i), (ii), and (iii), wherein steps (i) and (ii) are the same as in Example 1, the only difference being step (iii). Specifically, in this example, step (iii) is as follows: Step (iii): Preparation of compound 1 (compound 1, i.e., (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate tert-butyl ester), the synthesis method is as follows: 120 g of compound b (0.44 mol) and 600 g of tetrahydrofuran were added to a reaction flask. After stirring and dissolving, the mixture was cooled to 0-5 °C, and 1330 ml of borane dimethyl sulfide solution (concentration 1.0 mol / L, containing 1.33 mol of borane) was added dropwise under controlled temperature, and the reaction was allowed to proceed for 3-4 h. After the reaction of the starting materials was confirmed to be complete by HPLC, 120 g of water was added to quench the reaction, and then the tetrahydrofuran was removed by concentration. 240 g of DCM was added to the residue, and the mixture was cooled to 0-5 °C. Then, it was acidified with 1N hydrochloric acid, separated, and the aqueous phase was alkalized with ammonia. Then, 480 g of methyl tert-butyl ether was added for extraction. The obtained organic phase was concentrated with methyl tert-butyl ether under reduced pressure, and then 360 g of n-heptane was added for slurrying. The slurrying temperature was 0-5 °C, the stirring speed was 200-300 rpm, and the slurrying time was 30 min. The mother liquor showed almost no target product. The sample was then filtered and dried to obtain 96.1 g of a white solid (0.35 mol) of the title compound, with a yield of 79.0%, an HPLC purity of 97.9%, and a melting point of 86.3–87.4 °C.

[0047] In Examples 1 and 2 above, borane tetrahydrofuran and borane dimethyl sulfide were used as hydrogen sources, respectively. These methods not only achieved high reaction yields and mild conditions but also avoided the dependence on precious metal catalysts (such as palladium hydroxide) found in existing technologies. In comparison, borane dimethyl sulfide is unsuitable for production applications due to its odor problem. Therefore, borane tetrahydrofuran is the optimal choice for the industrial-scale production of this invention.

[0048] Comparative Example 1 The purpose of this comparative example is to verify the yield of compound 1 synthesized using existing techniques. The specific reaction process is as follows: (1) The preparation process of (S)-4-amino-3-((tert-butoxycarbonyl)amino)butyrate (i.e., compound of formula 1) disclosed in the prior art CN103080088A was carried out in the experiment, and the post-processing steps in its description were followed. The results are as follows: Step 1-1: Synthesize compound a 360 g of the starting material tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester (1.24 mol) and 1080 g of dimethylformamide were added to a reaction flask and stirred at 20-30 °C to dissolve. Then, 353 g of Boc anhydride (1.62 mol) and 124 g of ammonium bicarbonate (1.57 mol) were added, followed by dropwise addition of 61 g of pyridine (0.77 mol). The mixture was reacted for 3 h. After the reaction was complete, 1800 ml of toluene and 1440 ml of water were added, and the mixture was stirred and extracted for 30 min. The liquid was separated. The HPLC purity was 84.3%. The obtained organic phase was concentrated under reduced pressure until the flow stopped, yielding 370 g of a pale yellow product. This compound was not further purified and was used directly in the next reaction.

[0049] Steps 1-2: Synthesis of compound b 370 g of unpurified compound a (1.28 mol) obtained in Example 1-1 and 1020 g of DMF were added to a reaction flask and stirred until dissolved. Then, 112 g of cyanuric chloride (0.61 mol) was added in portions below 25 °C. The reaction solution was stirred at room temperature for 1 h. After the reaction was complete, 1850 g of 0.1 N NaOH solution and 1860 ml of toluene were added to the reaction solution and stirred for extraction. The mixture was separated, and the organic phase was washed once with 700 g of water. The organic phase was concentrated under reduced pressure until the flow was interrupted to obtain 322 g of the title compound (b). The overall yield of the two steps was 95.7%, and the HPLC purity was 50.7%. This compound was not further purified and was used directly in the next reaction.

[0050] Steps 1-3: Synthesize compound 1 200g of the unpurified compound of formula b obtained in Examples 1-2 and 4000ml of acetic acid were added to a hydrogenation reactor. After dissolution, 1.04g of 20% Pd(OH)2 was added. The mixture was reacted for 8 hours at a controlled temperature below 45°C and a hydrogen pressure of 3 atm. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetic acid, then diluted with 600ml of toluene and filtered through diatomaceous earth. 1060ml of 0.25N hydrochloric acid aqueous solution was added to the filtrate, and the mixture was stirred and extracted. The aqueous phase was alkalized with ammonia and then extracted with 1000ml of methyl tert-butyl ether. The obtained organic phase was concentrated under reduced pressure until the flow stopped to give 83g of the title compound (0.30mol), with a yield of 40.9% and an HPLC purity of 88.5%.

[0051] In this experiment, the reaction and post-processing were carried out according to the method described in CN103080088A. Although the literature reported a high yield, the applicant found that the scale-up effect of the process was significant when strictly repeating the disclosed examples (feed amount 200g). Due to the lack of purification of intermediates, impurities accumulated, which seriously affected the efficiency of the final catalytic hydrogenation, and the yield dropped sharply to about 40%, with unstable results. This reveals that the process in the literature is not reliable for industrial scale-up because the intermediates in each step were not purified before the next step, resulting in contamination of each reaction step and thus the yield of the final product was too low to be industrially produced.

[0052] Comparative Example 2: Process Yield under Existing Technology with Deep Purification of Raw Materials The purpose of this comparative example is to verify the effect of adding a purification step for the reaction intermediate on the final yield based on existing technology, as detailed below: Compound of Formula 1 The unpurified compound b obtained in steps 1-2 of Comparative Example 1 (HPLC purity 30.7%) was subjected to column chromatography and multiple recrystallizations for deep purification, and the HPLC purity after purification was 95.1%.

[0053] Then, 10 g of the deeply purified compound b (0.035 mol) and 200 ml of acetic acid were added to a hydrogenation reactor. After dissolution, 0.05 g of 20% Pd(OH)₂ was added. The mixture was reacted for 8 h at a controlled temperature below 45 °C and a hydrogen pressure of 3 atm. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetic acid, then diluted with 30 ml of toluene, and filtered through diatomaceous earth. 50 ml of 0.25 N hydrochloric acid aqueous solution was added to the filtrate, and the mixture was stirred and extracted. The aqueous phase was alkalized with ammonia and then extracted with 50 ml of methyl tert-butyl ether. The obtained organic phase was concentrated under reduced pressure until the flow stopped to give 8.2 g of the title compound (0.03 mol), with a yield of 80.4% and an HPLC purity of 93.2%.

[0054] In the above reaction, the reaction products of each step were deeply purified, and the yields were comparable to those in the reference. The above experimental results show that in the existing technical method, deep purification is required between each step. However, this deep purification operation can only be completed on a small scale and is not feasible for industrial production. Therefore, it is necessary to develop a method more suitable for industrial production.

[0055] Comparative Examples 1 and 2 show that Comparative Example 1 strictly followed the existing technology (CN103080088A), conducting a continuous reaction without purifying the intermediates in each step. Experimental results indicate that this method yields a low final product yield (40.3%) and lacks superior product purity. This is mainly because impurities carried by the intermediates may interfere with the reaction in subsequent steps, increase byproducts, and affect the final separation efficiency.

[0056] Comparative Example 2, based on the same route, involved meticulous and deep purification of the key intermediate (compound b). The results showed that, under conditions of obtaining a high-purity intermediate, the final yield reached 80.4%. This confirms that the synthetic route has good yield potential under ideal purification conditions, but it also highlights the practical challenges in its process: achieving this yield is highly dependent on purification operations that are difficult to scale up, such as column chromatography and multiple recrystallizations.

[0057] In summary, the existing technical solution presents a clear contradiction: it is valid in terms of the chemical pathway, but lacks feasibility in terms of the production process. Achieving high yields requires complex, in-depth purification, which faces multiple constraints in terms of efficiency, cost, and operational feasibility during industrial scale-up. Therefore, developing an alternative process that does not rely on in-depth purification, whose intermediates are easy to handle, and whose overall yield and purity meet production requirements has clear technical necessity and practical value.

[0058] Comparative Example 3: Effect of Solvent Selection on Yield during Pulping In the post-processing steps of the compounds of Formula 1 in various embodiments of the present invention, the product is purified by pulping. The applicant has screened the solvents used in this operation. Taking Example 1 as an example, with all other operations being the same, different solvents were selected for pulping, and the results are shown in Table 1: Table 1. Effect of solvent selection during pulping on product yield and purity. Experimental results show that water washing is the most common and simple post-treatment method, but it can only remove polar impurities, resulting in low purity. Other solvents used for pulping, due to differences in polarity and solubility, cannot simultaneously achieve high precipitation rates and high impurity removal rates. While petroleum ether and n-heptane are both low-grade aliphatic hydrocarbon solvents with comparable yields and high purity, petroleum ether has a very low flash point, posing a higher risk, and its complex composition is unfavorable for drug research; therefore, it is largely prohibited in production. In contrast, n-heptane pulping achieves the effect of "precipitating the target substance from a poor solvent + dissolving impurities," simultaneously removing both polar and non-polar impurities, making it more targeted and safer. Therefore, this invention uses n-heptane as the solvent, significantly improving the reaction yield.

[0059] Comparative Example 4 This comparative example aims to systematically investigate the effects of different hydrogen sources and their amounts on the yield and purity of the reduction reaction in step (iii), in order to determine the optimal reduction system for industrial production. The specific experimental design and results are shown in the table below (except for the variables listed in the table, all other reaction and post-treatment conditions are the same as in Example 1): Table 2. Effects of hydrogen source type and dosage on reaction yield and purity. The experimental results above show that, according to the results of the Comparative Examples A (A1-A4), the type of hydrogen source is a key factor affecting the efficiency of this reduction step. Commonly used mild reducing agents, sodium borohydride (NaBH4, Comparative Example A1) and sodium cyanoborohydride (NaBH3CN, Comparative Example A2), are insufficiently active in this reaction system; even under excess conditions, the yields are below 40% and 30%, respectively, and the product purity is poor. While the strong reducing agent lithium aluminum hydride (LiAlH4, Comparative Example A3) can partially reduce the amine, its vigorous and poorly selective nature results in an extremely low yield (approximately 15%) and numerous byproducts. Diisobutylaluminum hydride (DIBAL-H, Comparative Example A4) completely deviates from the target reaction pathway, its selectivity tends to reduce the amide to an aldehyde, almost completely failing to yield the target amine product. These results fully demonstrate that conventional non-borane reducing agents are unsuitable for the key reduction step of this invention.

[0060] Comparative Examples B (B1-B5) focused on optimizing the stoichiometric ratio of borane to tetrahydrofuran. Data showed that the amount of reducing agent was directly related to the reaction efficiency. When the amount was insufficient (molar ratio 2:1, Comparative Example B1), the yield (66.8%) and purity (94.5%) were significantly lower than the optimal values. When the molar ratio was increased to 2.5:1 (Comparative Example B2), the yield (70.5%) and purity (96.6%) improved, but still did not reach the optimal level. When the molar ratio was 3:1 (Comparative Example B3, i.e., Example 1), both the yield (80.3%) and purity (98.2%) reached their highest points. Further increasing the amount to 4:1 or 5:1 (Comparative Examples B4-B5) did not further increase the yield or purity, indicating that excess reducing agent had no beneficial effect.

[0061] The comparative experimental results show that the amide reduction reaction in this step is highly selective for the hydrogen source, and the borane complex is the only effective choice for achieving high yield and high purity conversion. Furthermore, there is a clear optimal ratio (3:1 equivalent). Below this ratio, the reaction is incomplete; above this ratio, it does not improve yield and purity but instead increases cost and post-processing difficulty. This provides clear, reliable, and economical process parameters for the industrial implementation of this invention.

[0062] The experimental results show that: using sodium borohydride as the hydrogen source results in mild reaction conditions but low yield and many byproducts, making purification difficult; using lithium aluminum hydride as the hydrogen source results in too strong reducing properties and more complex reactions, and the material is also highly hazardous, flammable in contact with water, and requires high moisture content; boranetetrahydrofuran has a higher reaction yield and purity, and is simpler to operate with a milder reaction. Therefore, this invention ultimately prefers boranetetrahydrofuran as the hydrogen source.

[0063] According to the process route designed in this invention, the reaction conditions requiring high-pressure hydrogenation under highly corrosive conditions are eliminated. The equipment is readily available, the reaction conditions are mild, the operation is simple, the reaction time is shortened, and the yield can reach about 80%, making it more suitable for industrial production.

[0064] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

[0065] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a gilgliptin intermediate compound, characterized in that, The structure of the gilgliptin intermediate compound is shown in Formula 1: Formula 1 The preparation method of the compound of Formula 1 includes the following steps: (i) In the presence of an organic base, tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester is reacted with a nitrogen source to obtain compound a; (ii) The compound of formula a is reacted with cyanuric chloride to obtain the compound of formula b; (iii) The compound of formula b is reacted with a hydrogen source to obtain the compound of formula 1.

2. The preparation method according to claim 1, characterized in that, In step (iii), the hydrogen source is selected from the group consisting of borane tetrahydrofuran, borane dimethyl sulfide, or combinations thereof.

3. The preparation method according to claim 1, characterized in that, Step (iii) is carried out in an organic solvent, preferably selected from the group consisting of tetrahydrofuran, dichloromethane, or combinations thereof.

4. The preparation method according to claim 1, characterized in that, In step (iii), the molar ratio of the hydrogen source to the compound of formula b is (2~5):

1.

5. The preparation method according to claim 1, characterized in that, Step (iii) includes: 1) A solution containing compound b is reacted with a hydrogen source to obtain a reaction mixture; 2) The reaction mixture is post-treated to obtain pharmaceutical intermediate compound of formula 1.

6. The preparation method according to claim 1, characterized in that, In step (i), the nitrogen source is selected from the group consisting of ammonia, ammonium bicarbonate, or a combination thereof.

7. The preparation method according to claim 1, characterized in that, In step (i), the organic base is pyridine.

8. The preparation method according to claim 1, characterized in that, In step (i), the reaction is carried out in an organic solvent; preferably, the solvent is selected from the group consisting of pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

9. The preparation method according to claim 1, characterized in that, In step (ii), the reaction is carried out in an organic solvent; preferably, the organic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

10. A method for preparing a compound of Formula 1, comprising the following steps: The compound of formula b was reacted with boranetetrahydrofuran to obtain the compound of formula 1.

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