Cystamine derivative impurity of tiagliptin hydrobromide and control method of cystamine derivative impurity

Abstract

The invention belongs to the field of medicines, and particularly discloses a cystamine derivative impurity of tiagliptin hydrobromide and a control method thereof, and the control method comprises the following steps: dissolving a starting material tetrahydrothiazole in an organic solvent, washing with water, stirring, standing, separating liquid, retaining an organic phase, and spin-drying to obtain purified tetrahydrothiazole. Compared with the prior art, the method has the advantages that cysteamine and cystamine impurities in the thiazolidine are reduced by washing and extracting the starting material thiazolidine, so that the content of cystamine derivative impurities in the tiagliptin API is less than 0.1%, the product purity is effectively improved, and the quality consistency of tiagliptin raw material medicines in multi-batch production is better; repeated recrystallization of API is avoided, the yield is increased to 80% from 36%, and the production cost is reduced; the operation is simple and easy to realize.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and particularly relates to a cystamine-derived impurity of tenegliptin hydrobromide and a control method thereof. Background Art

[0002] With the reduction of physical activity and unhealthy diet, diabetes has become a disease that seriously endangers human health. The prevention and treatment of diabetes has become one of the important and urgent medical and health care issues, so the research and development of diabetes drugs has also become the focus of the current pharmaceutical industry. There are five main types of diabetes drugs: insulin and insulin analogs, insulin secretion enhancers, insulin sensitizers, α-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors (DPP-IV inhibitors).

[0003] As a new type of hypoglycemic drug, DPP-Ⅳ inhibitors have certain advantages over other current hypoglycemic drugs. Tenegliptin is a DPP-Ⅳ inhibitor oral hypoglycemic drug developed by Mitsubishi Tanabe Pharma Co., Ltd. in Japan. It is mainly used clinically to treat type 2 diabetes. Tenegliptin reduces the inactivation of glucagon-like peptide in the body by inhibiting the activity of DPP-Ⅳ, while promoting the production of insulin by pancreatic cells, it can reduce the concentration of glucagon, thereby lowering blood sugar. The drug has good tolerance, a low incidence of adverse reactions, no adverse reactions such as hypoglycemia and weight gain, and combined use also has a significant hypoglycemic effect.

[0004] At present, the synthesis method of tenegliptin hydrobromide is relatively mature, but there are few reports on its impurities and impurity control methods. The starting material of tenegliptin, tetrahydrothiazole, has an acetal structure, which is unstable and easily self-degraded to produce cysteamine; the thiol group where cysteamine is located is extremely easy to form a more stable disulfide bond to convert into cystamine. Cysteamine and cystamine impurities will react with intermediates in each step and be transferred to the final product to form final derivative impurities, resulting in unstable quality of tenegliptin raw materials. Although the derivative impurities can be reduced to less than 0.1% through multiple recrystallization methods, the yield is reduced from 80% to 36%, the yield is greatly reduced, and the production cost is greatly increased. Summary of the invention

[0005] In view of the deficiencies in the prior art, the object of the present invention is to provide a cystamine-derived impurity of tenegliptin hydrobromide and a method for controlling the same. By washing and extracting the starting raw material tetrahydrothiazole, cysteamine and cystamine impurities therein are reduced, thereby reducing the content of cystamine-derived impurities in the tenegliptin finished product, thereby obtaining an API with stable quality. The operation is simple and easy to implement, and the product purity and yield are effectively improved, the production cost is reduced, and the problems in the background technology can be effectively solved.

[0006] The present invention is achieved through the following technical solutions: A cystamine-derived impurity of tenegliptin hydrobromide, having the following structure:

[0007] A further improvement of the present invention is: A method for controlling cystamine-derived impurities in tenegliptin hydrobromide comprises the following steps: dissolving a starting material tetrahydrothiazole in an organic solvent, washing with water, stirring and then standing, separating the liquids, retaining an organic phase, and drying by rotation to obtain purified tetrahydrothiazole.

[0008] Furthermore, the organic solvent is dichloromethane.

[0009] Furthermore, the volume ratio of dichloromethane to tetrahydrothiazole is 11-9:1.

[0010] Furthermore, the volume ratio of dichloromethane to tetrahydrothiazole is 10:1.

[0011] Furthermore, the water washing is performed twice, and the volume ratio of water to tetrahydrothiazole is 1-3:1 each time.

[0012] Furthermore, the stirring time is 3-8 min.

[0013] Furthermore, the standing time is 8-12 minutes.

[0014] Furthermore, the spin drying temperature is 20-30°C. Beneficial Effects

[0015] Compared with the prior art, the present invention has the following obvious advantages: 1. The present invention reduces the cysteamine and cystamine impurities in the starting raw material tetrahydrothiazole by washing and extracting, thereby effectively reducing the content of cystamine-derived impurities in the finished product of tenegliptin. After multiple batches of verification, the quality consistency of the finished product of tenegliptin is good (the impurity content can be controlled below 0.1%), effectively avoiding the appearance of unqualified finished products.

[0016] 2. The present invention washes and extracts the starting raw material tetrahydrothiazole, so that the final product can reduce the derived impurities to less than 0.1% after one recrystallization, effectively improving the production efficiency, increasing the yield from 36% to more than 80%, and greatly reducing the production cost.

[0017] 3. The present invention uses dichloromethane as an extractant in the tetrahydrothiazole extraction process. The reaction of tetrahydrothiazole and dichloromethane will introduce a small amount of dimer impurities. The dimer impurities do not participate in subsequent chemical reactions and are liquids themselves, so they are easily removed along with the crystallization mother liquor and have no effect on the overall process.

[0018] Fourth, the present invention is simple to operate and easy to implement. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is a mass spectrum of cystamine-derived impurities of tenegliptin hydrobromide in Example 1; Figure 2 is the cystamine-derived impurity of tenegliptin hydrobromide in Example 1 1 HNMR spectrum; Figure 3 The HPLC spectrum of the purified tetrahydrothiazole in Example 2 is shown in FIG. DETAILED DESCRIPTION

[0020] The present invention is described in detail below in conjunction with embodiments.

[0021] Example 1: Verification of Cystamine-derived Impurities in Tenegliptin Hydrobromide The synthesis of tenegliptin hydrobromide is carried out by the method recorded in the prior art, and the synthesis route is as follows:

[0022] The process is: S1, using compound 1 as a starting material, oxidizing the hydroxyl group to obtain compound 2; S2, subjecting compound 2 and tetrahydrothiazole to acid-amine condensation to obtain compound 3; S3, reductively aminating compound 3 and compound 4 to obtain compound 5, and salifying compound 5 under the action of hydrobromic acid to obtain compound 6; S4. Compound 6 is crystallized to obtain a crude product of tenegliptin hydrobromide, and the crude product is refined to obtain a finished product of tenegliptin hydrobromide.

[0023] Through the detection of the finished product of tenegliptin hydrobromide, it was found that one impurity was difficult to remove. Three batches of products (TG-31-240824-4, TG-31-240910-4, and TG-31-240925-5) were selected for analysis.

[0024] 1. Detection of impurities Detection method: HPLC Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (such as Zorbax SB-C18, 4.6mm×150mm, 5μm or chromatographic column with equivalent performance), 0.05mol / L sodium perchlorate solution (adjust the pH value to 2.5 with perchloric acid)-acetonitrile (85:15) as mobile phase A, and 0.05mol / L sodium perchlorate solution (adjust the pH value to 2.5 with perchloric acid)-acetonitrile (50:50) as mobile phase B. Perform gradient elution according to Table 1 below, the flow rate is 1.0ml per minute, the column temperature is 40℃, the detection wavelength is 245nm, and the injection volume is 10μL.

[0025] Table 1

[0026] The results are shown in Table 2: Table 2

[0027] 2. Structural identification of impurities The impurity is separated and purified by medium pressure Flash. The impurity is tested by mass spectrometry and nuclear magnetic resonance. The mass spectrum is as follows: Figure 1 Its H NMR spectrum is shown in Figure 2 shown.

[0028] Depend on Figure 1 It can be seen that the relative molecular weight of the impurity is 826.42; analyze Figure 2 , obtain the NMR data of the impurity and determine the structure of the impurity as follows: .

[0029] 3. Source of impurities This impurity is a cystamine-derived impurity, and it is inferred that it originates from the starting material tetrahydrothiazole. The pathways for tetrahydrothiazole to produce cysteamine and cystamine impurities are as follows: cysteamine raw materials used in the preparation process of tetrahydrothiazole; tetrahydrothiazole has an acetal structure, which is unstable and easily self-degrades to produce cysteamine; the thiol group where cysteamine is located is extremely easy to form a more stable disulfide bond to be converted into cystamine.

[0030] 4. Formation of impurities The cysteamine and cystamine impurities generated from the starting material tetrahydrothiazole will react with the intermediates in each step and be transferred to the final product to form the final derivative impurities. The reaction process is as follows:

[0031] Comparative Example 1: Recrystallization and purification of crude tenegliptin hydrobromide by the original process According to the process described in the above-mentioned prior art, a crude product of tenegliptin hydrobromide was prepared, and the crude product of tenegliptin hydrobromide was recrystallized. During the recrystallization process, the impurity content and the finished product recovery rate were tested. The specific results are shown in Table 3.

[0032] Table 3

[0033] Example 2: Control of Cystamine-derived Impurities in Tenegliptin Hydrobromide (1) Wash and extract the starting material tetrahydrothiazole: Dissolve 1.088 kg of tetrahydrothiazole in 14.4 kg of dichloromethane and wash twice with water, adding 2 kg of domestic water each time. Stir for 5 minutes and let stand for 10 minutes. Separate the liquids, spin dry the dichloromethane phase at 20-30°C, and obtain 0.902 kg of purified tetrahydrothiazole. HPLC test of the purified tetrahydrothiazole is shown in Figure 3 The product purity is 99.25%, cysteamine is not detected, cystamine is 0.11%, and dimer impurities are 0.35%.

[0034] The dimer impurities here are produced by tetrahydrothiazole and dichloromethane, but the amount produced is very low, and the structure has no reaction site, does not participate in chemical reactions, is liquid, and can be easily removed with the crystallization mother liquor. Therefore, it has no impact on the overall process.

[0035]

[0036] (2) Take 20g of compound 1 (Boc-L-hydroxyproline) and 0.4g of TEMPO, dissolve them in 600mL of ethyl acetate, and cool the system to 0-10°C. Add 100mL (15wt%) of TCCA in ethyl acetate to the system, and control the temperature at 0-10°C during the addition. After the addition, stir the system for 2-3h. TLC detection shows that there is no residual raw material. Add 100mL of 15wt% sodium bisulfite aqueous solution to the system. After the addition, test the system for non-oxidizing property with starch potassium iodide paper. Filter the system, separate the aqueous phase, concentrate the ethyl acetate phase, add n-heptane to disperse the solid, filter with suction, and dry to obtain 14.6g of compound 2 solid.

[0037] (3) Take 10g of the solid compound 2 and 10.5g of DCC, dissolve them in 200mL of ethyl acetate, stir for 0.5h, and then cool the system to 0-10°C. The system temperature is controlled at 0-10°C, and 6g of the purified tetrahydrothiazole is added dropwise. After the addition is completed, the system is stirred at 0-10°C for 1-1.5h. After TLC detection shows that there is no residual raw material in the system, 3g of domestic water is added, stirred for 5min, filtered, and the aqueous phase is separated. The ethyl acetate phase is concentrated to 20-30mL remaining, heated to 60-70°C, stirred to dissolve, and 50mL of n-heptane is added dropwise to the system. After the addition is completed, the system is cooled to 0-10°C and stirred for 1h, filtered, and the filter cake is vacuum dried at 40-50°C to obtain 9.8g of solid compound 3.

[0038] (4) Take 8g of the solid compound 3, dissolve it in 200mL of toluene, add 0.5g of glacial acetic acid and 7g of compound 4, and stir at 20-30°C to dissolve. Add 15g of sodium triacetoxyborohydride to the system in batches, stir at room temperature for 2h after addition, add 4g of water to the system after TLC detection of no residual raw materials, and stir for 5min. Separate the liquids, concentrate the toluene phase to dryness, add 160mL of isopropanol to the concentrated toluene phase, and heat to 70-80°C. Add 17g of 48% hydrobromic acid dropwise to the system, and stir the system for 4h after addition. A large amount of white solid precipitates in the system. Filter, and dry the filter cake in vacuum at 40-50°C to obtain 12.3g of crude tiagliptin hydrobromide.

[0039] Take 12g of the crude product of tenegliptin hydrobromide and dissolve it in 30mL of methanol, heat it to 60-65℃ and stir to dissolve. Filter out the insoluble matter while hot, cool the filtrate to 0-10℃ and stir for 1h. Filter and dry the filter cake at 40-50℃ to obtain 9.6g of the finished solid of tenegliptin hydrobromide. The finished product is tested by HPLC, and the product purity is 99.88% and the target impurity is 0.03%.

[0040] The process conditions, quality and yield of Comparative Example 1 and this embodiment are compared, and the results are shown in Table 4 below: Table 4

[0041] Conclusion: Compared with the original process, the new process can effectively control the limit of cystamine-derived impurities in the synthesis of tenegliptin hydrobromide, reduce the number of recrystallization and purification of the final product, and improve the yield.

[0042] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A cystamine-derived impurity of tenegliptin hydrobromide, characterized in that: The structure is as follows:

2. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 1, characterized in that: The steps are as follows: dissolving the starting material tetrahydrothiazole in an organic solvent, washing with water, stirring and then standing, separating the liquids, retaining the organic phase, and spinning to dry to obtain purified tetrahydrothiazole.

3. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 2, characterized in that: The organic solvent is dichloromethane.

4. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 3, characterized in that: The volume ratio of the dichloromethane to tetrahydrothiazole is 11-9:

1.

5. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 4, characterized in that: The volume ratio of the dichloromethane to tetrahydrothiazole is 10:

1.

6. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 2, characterized in that: The water washing is performed twice, and the volume ratio of water to tetrahydrothiazole is 1-3:1 each time.

7. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 2, characterized in that: The stirring time is 3-8 min.

8. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 2, characterized in that: The standing time is 8-12 minutes.

9. The method for controlling cystamine-derived impurities in tenegliptin hydrobromide according to claim 2, characterized in that: The spin drying temperature is 20-30°C.

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