Preparation method of L-pyroglutamic acid etogliflozin intermediate

Abstract

The invention provides a preparation method of an L-pyroglutamic acid etogliflozin intermediate, and belongs to the technical field of pharmaceutical synthesizing.The preparation method comprises the following steps that S1, under the inert condition, a compound 6 is subjected to TMS protection removal under base catalysis, paraformaldehyde 5 is depolymerized under base catalysis to generate formaldehyde 3, then the compound 6 and paraformaldehyde 5 are subjected to an aldol condensation reaction in an alkaline system, and the compound 6 and the formaldehyde 3 are subjected to post-treatment to obtain the L-pyroglutamic acid etogliflozin intermediate. Generating a compound 2; and S2, under an inert condition, adding a reducing agent, and reducing the compound 2 under the action of the reducing agent to generate a compound 1, namely the L-pyroglutamic acid etogliflozin intermediate. The preparation method provided by the invention avoids generation of byproducts in a reaction system, reduces a refining step, and greatly improves the yield and purity of the product.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an L-pyroglutamic acid etogliptin intermediate. BACKGROUND

[0002] SGLT-2 inhibitors (such as etogliptin) and GLP-1 receptor agonists are two new types of hypoglycemic drugs that are highly concerned. Etogliptin tablets are sodium-glucose cotransporter 2 inhibitors, which reduce the reabsorption of glucose filtered by the kidney by inhibiting SGLT2, lower the renal threshold of glucose, and thus increase the excretion of urine glucose.

[0003] L-pyroglutamic acid etogliptin (as shown in the following synthetic route, the L-pyroglutamic acid co-crystal compound of compound 7), the chemical name of which is (1S, 2S, 3S, 4R, 5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-(hydroxymethyl)-6, 8-dioxabicyclo[3.2.1]octane-2, 3, 4-triol and (2S)-5-pyrrolidone-2-carboxylic acid co-crystal compound, was approved by FDA in December 2017 for type 2 diabetes. Etogliptin tablets are mainly used for the control of blood glucose in type 2 diabetes, which is beneficial to the gradual decrease of blood glucose and the recovery to a good state, and improves the symptoms of emaciation, polydipsia, polyuria and hyperphagia of the patient's body.

[0004] In the patent application with the publication number CN102149717A and the literature of American Chemical Society Journal Org. Process Res. Dev. 2014, Vol. 18, pages 57-65, the preparation method of compound 7 disclosed mainly synthesizes compound 7 through the following route: .

[0005] In the patent application with the publication number CN102149717A, the method for synthesizing compound 1 in the above synthetic route is disclosed, which uses ethanol as a solvent, a potassium phosphate aqueous solution as a base, and compound 6 and a formaldehyde aqueous solution are first reacted at 55℃ for 24h, and then the temperature is increased to 70℃ for 12h. However, due to the high reaction temperature and long reaction time, in addition to the main reaction, a redox side reaction occurs in the system, in which 4 acts as an oxidizing agent and 3 acts as a reducing agent, a large amount of impurity 9 is generated (the ratio of compound 1 to impurity 9 in the reaction solution is about 1:1), and the chemical structural formula of impurity 9 is as follows: ; since a large amount of by-products are generated in the reaction, and impurity 9 is not easy to remove, multiple purification and impurity removal are required before further feeding, and the yield of obtained compound 1 is very low.

[0006] A method for preparing compound 1 is disclosed in J. Org. Process Res. Dev. 2014, 18, 57-65, which uses ethanol as solvent, sodium ethoxide as base, and reacts at 55℃ for 4h, and the selectivity of the reaction is improved, but since the reaction temperature is still high, in addition to the main reaction, 4 will undergo disproportionation reaction under this reaction condition, generating a large amount of impurities 8 and impurities 9, and the structural formula of impurities 8 is as follows: The ratio of compound 1, impurities 8 and impurities 9 in the reaction solution is about 7:1:2, and since a large amount of by-products are generated in the reaction, the obtained compound 1 needs to be refined before being further fed, which leads to a low yield of compound 1.

[0007] In summary, the prior art has obvious deficiencies, therefore, it is of great significance to develop a preparation method of L-pyroglutamic acid etogliptin intermediate with less impurities, simple operation, high product yield and purity. SUMMARY

[0008] The present application provides a preparation method of L-pyroglutamic acid etogliptin intermediate, which avoids the generation of by-products in the reaction system, reduces the refining step, and greatly improves the yield and purity of the product.

[0009] The technical scheme for solving the above technical problems is as follows: a preparation method of L-pyroglutamic acid etogliptin intermediate, the preparation method comprising the following steps: S1, under inert conditions, compound 6 is deprotected under the catalysis of a base, and paraformaldehyde 5 is depolymerized to generate formaldehyde 3 under the catalysis of a base, and then the two undergo aldol condensation reaction in a basic system to generate compound 2; S2, under inert conditions, a reducing agent is added, and compound 2 is reduced to generate compound 1, i.e. L-pyroglutamic acid etogliptin intermediate, under the action of the reducing agent.

[0010] Further, after the reaction of step S1 is completed, the generated compound 2 can be separated out for step S2, or can be directly put into step S2 without separation, to realize one-pot reaction.

[0011] Further, in step S1, the molar ratio of compound 6, paraformaldehyde 5 and base is 1: (1.5-5): (1-2.5).

[0012] Further, in step S2, the molar ratio of compound 6 and the reducing agent is 1: (0.5-2).

[0013] Further, in step S1, the reaction temperature is 10-40℃, preferably 25-35℃.

[0014] Further, in step S2, the reaction temperature is -10-30℃, preferably 0-10℃.

[0015] Further, in step S1, the base is at least one of potassium hydroxide, sodium hydroxide, sodium carbonate, barium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, preferably at least one of sodium methoxide and sodium ethoxide.

[0016] Further, in step S1, the reaction solvent is at least one of C1-C3 alcohol, 1,2-propanediol, glycerol, isopropyl alcohol, dichloromethane, toluene, C2-C3 nitrile, preferably methanol or ethanol.

[0017] Further, in step S2, the reducing agent is at least one of lithium aluminum hydride, alkoxy-substituted lithium aluminum hydride, sodium borohydride, alkoxy-substituted sodium borohydride, aluminum isopropyl alcohol.

[0018] Further, in step S2, the reaction solvent is at least one of C1-C3 alcohol, 1,2-propanediol, glycerol, isopropyl alcohol, dichloromethane, toluene, C2-C3 nitrile, preferably methanol or ethanol.

[0019] Further, the present application provides a preparation method of L-pyroglutamic acid etogliptin intermediate, and the L-pyroglutamic acid etogliptin intermediate obtained by the method is used for preparing a synthetic intermediate of compound 7 or a co-crystal of compound 7, wherein the chemical structural formula of the compound 7 is as follows: .

[0020] The present application has the following beneficial effects: (1) The preparation method of L-pyroglutamic acid etogliptin intermediate provided by the present application uses compound 6 and paraformaldehyde 5 as starting materials, adopts a one-pot method or a step-controllable strategy, realizes high selectivity of the entire reaction process through precise control of the reaction conditions, and reduces the generation of impurities 8 and 9.

[0021] (2) The synthetic route of the preparation method of L-pyroglutamic acid etogliptin intermediate provided by the present application is simple and easy to operate, and the purity of the finally obtained product is higher than 99.8%, which is much higher than the yield and purity in the prior art, avoids the refining step, greatly improves the yield and purity of the product, and is simple to operate and suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 It is an HPLC spectrum of compound 1 in Example 1; Figure 2 It is a nuclear magnetic hydrogen spectrum spectrum of compound 1 in Example 1; Figure 3 It is a nuclear magnetic carbon spectrum spectrum of compound 1 in Example 1. DETAILED DESCRIPTION

[0023] The specific embodiments of the present application will be described in detail below. The present application can be implemented in many different ways than described herein, and those skilled in the art can make similar improvements without departing from the spirit of the present application, so the present application is not limited by the disclosed specific embodiments.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used only for the purpose of describing specific embodiments, not for limiting the present application.

[0025] The present application provides a preparation method of an L-pyroglutamic acid etogliptin intermediate, the preparation method comprising the following steps: S1, under inert conditions, compound 6 is deprotected under the catalysis of a base, and paraformaldehyde 5 is depolymerized under the catalysis of a base to generate formaldehyde 3, and then the two are subjected to aldol condensation reaction in an alkaline system with the temperature controlled at 10-40℃ to generate compound 2; S2, under inert conditions, the reaction temperature is controlled at-10-30℃, a reducing agent is added, and compound 2 is reduced by the reducing agent to generate compound 1 ((2S, 3R, 4S, 5S)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6, 6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3, 4, 5-triol)), which is an L-pyroglutamic acid etogliptin intermediate.

[0026] The chemical synthesis route involved in the above preparation method is as follows: S1,

[0027] S2, .

[0028] Specifically, after the reaction of step S1 is completed, the generated compound 2 can be separated out for step S2, or can be directly subjected to step S2 without separation, to realize one-pot reaction.

[0029] The existing method generally uses formaldehyde aqueous solution and performs the reaction at a relatively high temperature (55℃ or above), which leads to two main side reactions in the system: one is that formaldehyde (as a reducing agent) and compound 4 (as an oxidizing agent) generated in the reaction undergoes redox reaction to generate a large amount of by-product impurity 9, and the chemical structural formula of impurity 9 is as follows: ; and the other is that compound 4 undergoes disproportionation reaction under the environment of strong base and high temperature, thereby interfering with the progress of the main reaction, to generate a large amount of impurities 8 and 9, and the structural formula of impurity 8 is as follows: These side reactions not only reduce the selectivity of the main reaction, leading to a decrease in product purity, but also require multiple purification steps, which seriously affect the yield and industrial feasibility. In the design of the entire route in the prior art, the generation of compound 2 (the chemical structure of compound 2 is as follows: ) is far slower than the generation of compound 2 to generate compound 1, and compound 2 itself will undergo disproportionation under the action of strong base to generate a series of impurities; the prior art hardly observes compound 2 during the reaction process. Based on this, the present application precisely controls the reaction to generate compound 2 in step S1, with almost no by-product generated, and in step S2, compound 2 is precisely reduced to generate compound 1, with almost no by-product generated, thereby improving the selectivity of the entire reaction process.

[0030] The present application uses solid paraformaldehyde instead of aqueous formaldehyde solution as a reaction raw material. The depolymerization rate of paraformaldehyde in the reaction system of the present application is controllable, and formaldehyde monomers are slowly released during the reaction process, so that the formaldehyde concentration is maintained at a low level, thereby effectively inhibiting the redox reaction of formaldehyde and the excessive side reaction with other intermediates. Step S1 greatly reduces the reaction temperature, and the reaction temperature is controlled at 10-40°C (preferably 25-35°C), which is much lower than the 55-70°C of the prior art. Low temperature conditions inhibit side reactions, reduce the generation of thermodynamically driven by-products, and reduce the redox side reactions of compound 4 as an oxidizing agent and formaldehyde as a reducing agent in the existing synthesis method, as well as the formation of impurities 8 and 9 generated by the disproportionation reaction of compound 4. The present application uses a "one-pot" or stepwise controllable strategy. The present application allows compound 2 to be directly reduced to compound 1 in the same reaction system without separation, not only reducing the loss caused by the separation of intermediate 2, but also avoiding the side reactions that may occur during the separation process. At the same time, the "one-pot" method reduces the complexity of the operation, improves the overall economy and operational efficiency.

[0031] The core mechanism of the present application is to utilize the controllable and slow depolymerization characteristics of paraformaldehyde in alkaline medium, so that the concentration of free formaldehyde in the reaction system is always maintained at a low level, which on the one hand inhibits the tendency of formaldehyde as a reducing agent to undergo redox reaction, thereby cutting off the key source of impurity 9, creating a window for the improvement of reaction selectivity. At the same time, the reaction temperature is greatly reduced from the existing technology of more than 55℃ to the mild interval of 10-40℃, which inhibits all side reaction channels involving high activation energy from the energy level, especially significantly reduces the rate of disproportionation reaction, so that the main reaction path occupies an absolute advantage in kinetics. The one-pot process design not only naturally adapts to the above mild reaction conditions, but also reduces the loss of intermediate compound 2 in the separation and drying process by avoiding the separation and purification of intermediate compound 2, reduces the risk of possible side reactions, and realizes the closure of the reaction system and efficient conversion of materials.

[0032] Specifically, in step S1, the molar ratio of compound 6, paraformaldehyde 5 and base is 1: (1.5-5): (1-2.5).

[0033] Specifically, in step S2, the molar ratio of compound 6 and the reducing agent is 1: (0.5-2).

[0034] Specifically, in step S1, the reaction temperature is 10-40℃, preferably 25-35℃.

[0035] Specifically, in step S2, the reaction temperature is -10-30℃, preferably 0-10℃.

[0036] Specifically, in step S1, the base is at least one of potassium hydroxide, sodium hydroxide, sodium carbonate, barium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide, preferably at least one of sodium methoxide and sodium ethoxide.

[0037] Specifically, in step S1, the reaction solvent is at least one of C1-C3 alcohol, 1,2-propanediol, glycerol, isopropyl alcohol, dichloromethane, toluene, and C2-C3 nitrile, preferably methanol or ethanol.

[0038] Specifically, in step S2, the reducing agent is at least one of lithium aluminum hydride, alkoxy-substituted lithium aluminum hydride, sodium borohydride, alkoxy-substituted sodium borohydride, and aluminum isopropylate.

[0039] Specifically, in step S2, the reaction solvent is at least one of C1-C3 alcohol, 1,2-propanediol, glycerol, isopropyl alcohol, dichloromethane, toluene, and C2-C3 nitrile, preferably methanol or ethanol.

[0040] More specifically, after the reaction of step S2 is completed, the post-treatment involves: concentrating the reaction solution at 40-50°C, adding ethyl acetate and saturated ammonium chloride aqueous solution to the concentrated residue, extracting and separating, collecting the organic phase, concentrating the organic phase at 40-50°C, adding methanol to the concentrated residue, stirring to dissolve, then adding compound 1 seed crystals, crystallizing for 4-6 hours, cooling to -20 to -10°C, filtering, collecting the filter cake, and drying under reduced pressure at 50-60°C.

[0041] Specifically, the present application provides a preparation method of L-pyroglutamic acid etogliptin intermediate, which is used to prepare compound 7 or a co-crystal of compound 7, wherein the chemical structural formula of compound 7 is as follows: .

[0042] Example 1 Preparation of L-pyroglutamic acid etogliptin intermediate, compound 1 ((2S, 3R, 4S, 5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol)): S1, under nitrogen protection, compound 6 (20.00 g, 30.61 mmol), anhydrous ethanol 140.00 g, and paraformaldehyde (1.38 g, 45.91 mmol) were added to a dry 500 mL three-necked flask, and then sodium methoxide (3.31 g, 61.22 mmol) was added under temperature control at 20-30°C, and then the reaction was continued for 9-12 hours under temperature control at 25-35°C, the system was a clear solution, and HPLC monitoring showed that the reaction of intermediate I was completed; S2, under nitrogen protection, the system was cooled to 0-10°C, and sodium borohydride (0.58 g, 15.30 mmol) was added to the system, HPLC monitoring showed that the reaction of intermediate II was completed, the HPLC spectrum of compound 1 is shown in Figure 1 , and the HPLC detection data are shown in Table 1.

[0043] Post-treatment: the reaction solution was concentrated at 40-50°C, ethyl acetate (100.00 g) and saturated ammonium chloride aqueous solution (100.00 g) were added to the concentrated residue, extraction and separation were performed, the organic phase was collected, the organic phase was concentrated at 40-50°C, methanol (80.00 g) was added to the concentrated residue, stirring was performed to dissolve, then compound 1 seed crystals were added, crystallization was performed for 4-6 hours, cooling was performed to -20 to -10°C, filtering was performed, the filter cake was collected, and drying was performed under reduced pressure at 50-60°C, to obtain 11.63 g of compound 1, with a yield of 81.0% and a purity of 99.866%.

[0044] The compound 1 was identified by high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectrum (1H-NMR), and nuclear magnetic resonance carbon spectrum (13C-NMR). 1H-NMR), carbon nuclear magnetic resonance (NMR) 13 The structure of compound 1 was confirmed by C1-NMR: ESI-HRMS: C1 23 H 29 ClO8[M-OMe] + :437.1362, found:437.1364.

[0045] 1 H-NMR (400MHz, MeOH-) d 4 ):7.521 (d, J= 2.0Hz, 1H, -C6H3-), 7.473 (dd, J=8.4 Hz, 2.4Hz, 1H, -C6H3-), 7.329 (d, J=8.4Hz, 1H, -C6H3-), 7.099-7.063 (m,2H, -C6H4-), 6.804-6.767 (m, 2H, -C6H4-), 4.175-4.146 (m, 1H, -C7H7-), 4.094-4.057 (m, 1H, -C7H7-), 4.000-3.908 (m, 4H+2H, -C7H7-&-C2H5), 3.839-3.810 (m,1H, -C7H7-), 3.780-3.755(m, 1H, -CH2-), 3.104 (s, 3H, -OCH3), 3.069-3.045 (m,1H, -CH2-), 1.342 (t, J=7.2Hz, 3H, -C2H5).

[0046] 13 C-NMR (100MHz, MeOH-d4) δ:157.466,138.732, 138.186, 133.424,131.708, 130.683, 129.447, 128.470, 127.080, 114.077, 102.261, 80.212,77.452, 72.335, 70.323, 64.152, 63.079, 62.149,49.893, 37.953, 13.892. The 1H NMR spectrum of compound 1 is shown below. Figure 2 The carbon spectral data of compound 1 can be found in [link to carbon spectral data]. Figure 3 .

[0047] Table 1. HPLC detection data of compound 1

[0048] Example 2 Preparation of L-pyroglutamic acid etogliptin intermediate, compound 1 ((2S, 3R, 4S, 5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol)): S1, under nitrogen protection, compound 6 (20.00 g, 30.61 mmol), methanol 180.00 g, paraformaldehyde (2.76 g, 91.82 mmol) were added into a dry 500 mL three-necked flask, sodium methoxide (2.48 g, 45.91 mmol) was added at a temperature of 20-30 °C, and then the reaction was continued at a temperature of 25-35 °C for 9-12 h. The system was a clear solution, and the reaction was completed according to HPLC monitoring. S2, under nitrogen protection, the system was cooled to 0-10 °C, and sodium borohydride (1.74 g, 45.91 mmol) was added into the system, and the reaction was completed according to HPLC monitoring.

[0049] Post-treatment: the reaction liquid was concentrated at 40-50 °C, ethyl acetate (80.00 g) and saturated ammonium chloride aqueous solution (120.00 g) were added into the concentrated residue, the organic phase was collected by liquid-liquid extraction, and the organic phase was concentrated at 40-50 °C. Methanol (60.00 g) was added into the concentrated residue, and compound 1 crystal seeds were added after stirring and dissolving. The system was crystallized for 4-6 h, cooled to -20--10 °C, filtered, and the filter cake was collected and dried under reduced pressure at 50-60 °C to obtain 11.40 g of compound 1, with a yield of 79.4% and a purity of 99.828%.

[0050] Example 3 Preparation of L-pyroglutamic acid etogliptin intermediate, compound 1 ((2S, 3R, 4S, 5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol)): S1, under nitrogen protection, compound 6 (20.00 g, 30.61 mmol), anhydrous ethanol 100.00 g, paraformaldehyde (1.84 g, 61.22 mmol) were added into a dry 500 mL three-necked flask, sodium methoxide (4.13 g, 76.52 mmol) was added at a temperature of 20-30 °C, and then the reaction was continued at a temperature of 25-35 °C for 9-12 h. The system was a clear solution, and the reaction was completed according to HPLC monitoring. S2, under nitrogen protection, the system was cooled to 0-10 °C, and sodium borohydride (6.49 g, 30.61 mmol) was added into the system, and the reaction was completed according to HPLC monitoring.

[0051] Post-treatment: the reaction solution was concentrated at 40-50℃, ethyl acetate (60.00g) and saturated ammonium chloride aqueous solution (80.00g) were added to the concentrated residue, the organic phase was collected by extraction and separation, the organic phase was concentrated at 40-50℃, methanol (100.00g) was added to the concentrated residue, after stirring and dissolving, compound 1 seed was added, the crystal was aged for 4-6 hours, the temperature was lowered to-20--10℃, filtration was performed, the filter cake was collected, and the filter cake was dried at 50-60℃ under reduced pressure to obtain 10.94g of compound 1, the yield was 76.2%, and the purity was 99.819%.

[0052] Example 4 Preparation of L-fornitrophenylalanine etogliptin intermediate, compound 1 ((2S, 3R, 4S, 5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol)): S1, under nitrogen protection, compound 6 (20.00g, 30.61mmol), methanol 120.00g, paraformaldehyde (4.60g, 153.03mmol) were added to a dry 500mL three-necked flask, sodium methoxide (4.13g, 76.52mmol) was added under temperature control at 20-30℃, then the reaction was continued under temperature control at 25-35℃ for 9-12h, the system was a clear solution, and HPLC monitoring showed that the reaction of intermediate I was completed. S2, under nitrogen protection, the system was cooled to 0-10℃, and sodium borohydride (2.32g, 61.22mmol) was added to the system, and HPLC monitoring showed that the reaction of intermediate II was completed.

[0053] Post-treatment: the reaction solution was concentrated at 40-50℃, ethyl acetate (60.00g) and saturated ammonium chloride aqueous solution (80.00g) were added to the concentrated residue, the organic phase was collected by extraction and separation, the organic phase was concentrated at 40-50℃, methanol (100.00g) was added to the concentrated residue, after stirring and dissolving, compound 1 seed was added, the crystal was aged for 4-6 hours, the temperature was lowered to-20--10℃, filtration was performed, the filter cake was collected, and the filter cake was dried at 50-60℃ under reduced pressure to obtain 10.94g of compound 1, the yield was 76.2%, and the purity was 99.819%.

[0054] Comparative Example 1 The difference between this comparative example 1 and the method provided by the present application is that the reaction temperature is controlled at 50-60℃, and the proportion of paraformaldehyde (compound 5) is increased (the molar ratio of compound 6 to compound 5 is 1:20), so that the depolymerized formaldehyde can not only undergo aldol condensation reaction, but also act as a reducing agent to reduce the aldehyde group of 2 to generate compound 1. The specific preparation process is as follows: (1) Under nitrogen protection, compound 6 (64.16 g), anhydrous ethanol (240.00 g), and paraformaldehyde (54.80 g) were added into the system, and the system was heated to 50-60°C. Then 20% sodium ethoxide solution (62.08 g) was added into the system, and the system was stirred at 50-60°C for 10 hours. Then sodium bisulfite aqueous solution (649.67 g) was added into the system, and the system was divided. The organic phase was concentrated under reduced pressure at 60°C. Then methyl tert-butyl ether (200.00 g) and water (200.00 g) were added into the system, and the system was divided. The organic phase was concentrated under reduced pressure at 50-60°C. Then methanol (200.00 g) was added into the system, and the system was stirred until it was clear. Then seed crystals were added, and the system was crystallized at -20--10 o C for 2 hours. The precipitated crystals were collected by filtration, and dried to obtain compound 1 crude product (28.20 g) with a yield of 66% and a purity of 95.5%.

[0055] (2) Under nitrogen protection, compound 1 crude product (28.20 g) and methanol (141.02 g) were added into the system, and the system was heated to 50-60°C. Then the system was stirred for 0.5 hours. Then the system was cooled to -20--10°C, and crystallized for 2 hours. The precipitated crystals were collected by filtration, and dried to obtain compound 1 (25.38 g) with a purity of 99.5% and a refined yield of 90%, and a total yield of 59.4%.

[0056] As can be seen from the experimental results of the examples and Comparative Example 1, the yield and purity of the L- pyroglutamic acid etogliptin intermediate (compound 1) prepared by the preparation method provided in the present application are higher. The method adopted in Comparative Example 1 has poor reaction selectivity in the preparation process, which leads to the generation of a large amount of impurities 8 and 9. The impurity 9 is difficult to remove. If the qualified final product is to be obtained, the compound 1 needs to be recrystallized, which seriously affects the yield of the final product. This is a preparation method that is difficult to realize industrialization and amplification. The preparation method described in the present application is simple and easy to operate, reduces the refining step, avoids the reaction selectivity problem of the existing process, is more suitable for industrial production, and the yield and purity of the target compound obtained are obviously higher than those of the existing process.

[0057] Comparative Example 2 The same method as in Example 1 was adopted in this comparative example 2, except that the reaction temperature in step S1 was controlled at 55°C. Finally, the yield of compound 1 was 65.4%, and the purity was 97.092%.

[0058] When the reaction temperature in step S1 is increased, compound 4 in step S1 generates compound 2, and also generates impurities 8 and 9 through self-disproportionation. Due to the high reaction temperature, compound 2 further generates compound 1 and other impurities, which further affects the purity and yield of compound 1 in step S2.

[0059] Comparative Example 3 The comparative example 3 uses the same method as example 1, except that the reaction temperature of step S1 is controlled at 5°C, and the final yield of compound 1 is 56.4% with a purity of 98.258%.

[0060] The comparative example 3 reduces the temperature to 5°C in step S1, which results in incomplete reaction in step S1, and the yield of compound 2 is low, which further affects the purity and yield of compound 1 in step S2.

[0061] Comparative example 4 The comparative example 4 uses the same method as example 1, except that in step S1, aqueous formaldehyde solution is used instead of paraformaldehyde in example 1, and the final yield of compound 1 is 55.2% with a purity of 96.523%.

[0062] The comparative example 4 replaces paraformaldehyde with aqueous formaldehyde solution in step S1, which results in too high concentration of formaldehyde in the system, increased impurity generation, and low purity of compound 2, which further affects the purity and yield of compound 1 in step S2.

[0063] Comparative example 5 The comparative example 5 uses the same method as example 1, except that in step S1, aqueous potassium phosphate solution commonly used in prior art is used as a base, and other amounts and reaction conditions are according to example 1. The final yield of compound 1 is 53.3% with a purity of 95.512%.

[0064] The comparative example 5 does not detect compound 2, and the yield and purity of compound 1 decrease, because when the base is replaced with the base in the prior art, the reaction in the reaction system is very complex, and does not stop at step S1 to generate compound 2, but directly generates compound 1 and a large amount of impurities according to the prior art route, and the yield decreases.

[0065] Comparative example 6 The comparative example 6 uses the same method as example 1, except that in step S1, sodium methoxide (6.61g, 122.43mol) is added, and the final yield of compound 1 is 67.1% with a purity of 98.271%.

[0066] The comparative example 6 uses too much base, which generates impurities, affecting the purity of compound 2, and further affecting the purity and yield of compound 1.

[0067] Comparative example 7 The comparative example 7 uses the same method as example 1, except that in step S1, paraformaldehyde (6.43g, 214.43mmol) is added, and the final yield of compound 1 is 66.9% with a purity of 97.909%.

[0068] The para example 7 uses too much paraformaldehyde, which makes too much depolymerized formaldehyde, and the formaldehyde can reduce compound 4 as a reducing agent, the main reaction selectivity is reduced, impurities are generated, the purity of compound 2 is affected, and then the purity and yield of compound 1 are affected.

[0069] Para example 8 The para example 8 uses the same method as example 1, except that the reaction temperature in step S2 is controlled at 45°C. The final yield of compound 1 is 69.7%, and the purity is 98.216%.

[0070] When the temperature of step S2 in the para example 8 is too high, compound 2 is unstable and has side reactions with formaldehyde. Compound 2 has both oxidizing and reducing properties, and itself has side reactions, which affects the yield and purity of compound 1.

[0071] The technical features of the above-described examples can be combined arbitrarily. In order to make the description simple, all possible combinations of the technical features in the above-described examples are not exhaustively listed, but as long as the combinations of the technical features do not contradict, they should be considered as within the scope of the present disclosure.

[0072] For those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which are within the scope of the present application. The scope of protection of the present application is subject to the appended claims.

Claims

1. A method for preparing an intermediate of L-pyroglutamic acid etogliptin, characterized by, The preparation method comprises the following steps: S1, under inert conditions, compound 6 is deprotected under catalysis of a base, paraformaldehyde 5 is depolymerized under catalysis of a base to generate formaldehyde 3, and then the two undergo aldol condensation reaction in a basic system to generate compound 2; S2, under inert conditions, a reducing agent is added, and compound 2 is reduced under action of the reducing agent to generate compound 1, i.e. an L-pyroglutamic acid etogliptin intermediate.

2. The method for preparing an intermediate of L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that, In step S1, the molar ratio of compound 6, paraformaldehyde 5 and the base is 1: (1.5-5): (1-2.5).

3. The method for preparing an intermediate of L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that, In step S2, the molar ratio of compound 6 and the reducing agent is 1: (0.5-2).

4. The method for preparing an intermediate of L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that, In step S1, the reaction temperature is 10-40℃.

5. The method for preparing an intermediate of L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that, In step S2, the reaction temperature is -10-30℃.

6. The method for preparing an intermediate of L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that, In step S1, the base is at least one of potassium hydroxide, sodium hydroxide, sodium carbonate, barium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.

7. The method for preparing an intermediate of L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that, In step S1, the reaction solvent is at least one of C1-C3 alcohol, 1,2-propanediol, glycerol, isopropanol, dichloromethane, toluene and C2-C3 nitrile. 8.The method for preparing an intermediate of L-pyroglutamic acid etogliptin according to claim 1, wherein, In step S2, the reducing agent is at least one of lithium aluminum hydride, alkoxy-substituted lithium aluminum hydride, sodium borohydride, alkoxy-substituted sodium borohydride and isopropanol aluminum. ​ 9.The method for preparing an intermediate of L-pyroglutamic acid etogliptin according to claim 1, wherein, In step S2, the reaction solvent is at least one of C1-C3 alcohol, 1,2-propanediol, glycerol, isopropanol, dichloromethane, toluene and C2-C3 nitrile. ​ 10.The method for preparing an intermediate of L-pyroglutamic acid etogliptin according to any one of claims 1-9, characterized in that, The L-pyroglutamic acid etogliptin intermediate prepared by the preparation method is used as a synthetic intermediate for preparing compound 7 or a co-crystal compound of compound 7, wherein the chemical structural formula of compound 7 is as follows: 。

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