CN111440145A - New crystal form of high-purity troxagliptin and its preparation - Google Patents

Abstract

The invention provides a novel high-purity trelagliptin crystal. The high-purity trelagliptin prepared by the method can form salt with acid to obtain high-purity trelagliptin salt, and simultaneously provides a preparation and purification crystallization process of high-purity trelagliptin crystals, and the preparation and purification crystallization process comprises the following steps:

Description

New crystal form of high-purity troxagliptin and its preparation

This application is a divisional application of a Chinese invention patent application (application date: November 25, 2014; application number: 201410692331.6; invention name: new crystal form of high-purity trilagliptin and its preparation).

technical field

The invention belongs to the field of chemical drug synthesis, and in particular relates to a high-purity new crystal form of a hypoglycemic drug-troglitatin and its preparation and application.

Background technique

Diabetes Mellitus (DM) is a metabolic disease with multiple etiologies. It is caused by the increase of blood sugar caused by the absolute or relative deficiency of insulin, which causes the metabolic disorder of the body. It can be divided into insulin-dependent diabetes mellitus (IDDM, also known as type I diabetes) and non-insulin dependent diabetes mellitus (NIDDM, also known as type II diabetes), of which type II diabetes The most common, accounting for more than 90% of diabetic patients. Dipeptidyl peptidase IV (DPP-IV) is a serine protease that is expressed in many tissues in the body, such as the intestine, liver, lung, kidney, etc., as well as in circulating T lymphocytes. It is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1(7-36), glucagon) in vivo and has been shown to be effective against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro proteolytic activity. GLP-1(7-36) is a 30 amino acid peptide derived from the post-translational processing of preglucagon in the small intestine. GLP-1(7-36) has a variety of in vivo effects, including stimulation of insulin secretion, inhibition of glucagon secretion, promotion of satiety, and delayed gastric emptying. Based on its physiological behavior, the action of GLP-I(7-36) is believed to be beneficial in the prevention and treatment of type II diabetes and obesity. For example, exogenous administration (continuous infusion) of GLP-1(7-36) in diabetic patients has been found to be effective in this patient population. Unfortunately, GLP-1(7-36) is rapidly degraded in vivo with a short half-life (t1/2<1.5min). Based on studies in genetically bred DPP-IV knockout mice and in vivo/in vitro studies of selective DPP-IV inhibitors, it has been shown that DPP-IV is the major degrading enzyme for GLP-1(7-36) in vivo. GLP-1(7-36) is efficiently degraded by DPP-IV to GLP-1(9-36), which is presumed to act as a physiological antagonist of GLP-1(7-36). It is therefore believed that inhibition of DPP-IV in vivo may serve to enhance endogenous GLP-1(7-36) levels and attenuate the production of its antagonist GLP-1(9-36). DPP-IV inhibitors can be used to treat or prevent or delay the progression of disorders mediated by DPP-IV, such as diabetes, especially type II diabetes.

Trolagliptin is an effective dipeptidyl peptidase IV (DPP-4) inhibitor developed by Takeda Pharmaceutical Co., Ltd., which can control blood sugar levels by selectively and persistently inhibiting DPP-4. The NDA submission for trelagliptin is based on efficacy and safety data from several Phase III clinical trials conducted in Japanese patients with type 2 diabetes. The efficacy of trelagliptin has been demonstrated in all trials, and it has a good safety and tolerability profile. Once-weekly administration of trelagliptin can effectively control blood sugar levels, which is expected to improve patients' medication compliance. It is understood that DPP-4 inhibitors are the first type of new type 2 diabetes drugs that can improve the body's own ability to control blood sugar levels. It can be used as a single drug or in combination with other oral hypoglycemic drugs. Its mechanism of action is unique, and it has unique advantages such as no hypoglycemia, no weight gain, and few side effects, and the incidence of gastrointestinal adverse reactions is also very low.

The chemical name for troxagliptin is 2-[{6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1(2H)-yl}methyl]-4-fluoro-benzyl cyanide; chemical formula is C ₁₈ H ₂₀ FN ₅ O ₂ .C ₄ H ₆ O ₄ ; CAS number is 865759-25-7.

Its structural formula is as follows:

Chinese patent CN102140090 discloses a method for preparing troxagliptin, as shown in the following route:

In the operation process of the above route, compound 1, ethanol and (R)-3-aminopiperidine dihydrochloride 2 were added into a closed tube, and a nucleophilic substitution reaction occurred at 100° C. to obtain the compound troxagliptin. Since the boiling point of ethanol is only 78°C, the heating under normal pressure can only reach the boiling point temperature, and the reaction temperature can be increased to a certain extent in a closed tube sealing operation; however, the tube sealing operation is difficult to scale up and apply to industrial production; The piperidine structure has both primary and secondary amine groups, and both the primary and secondary amine groups can compete with compound 1 for substitution reaction to generate positional isomer-compound 3, as shown in the following formula:

The research group conducted in-depth research on the method disclosed in the patent CN102140090. According to the disclosed method, the content of the positional isomer obtained after the reaction was greater than 4.6% (see Comparative Example 1). Since many positional isomers are generated in the reaction, purification treatment is required. The method reported in the patent CN102140090 is to use high performance liquid chromatography (HPLC) to purify and further prepare troxagliptin trifluoroacetate. If the free base of trolagliptin needs to be prepared, it is also necessary to alkalize the trifluoroacetic acid salt of troxagliptin; from the obtained free base of trolagliptin, other salts (such as: trolagliptin succinate) can be easily prepared Ting). In the above-mentioned documents, high-performance liquid chromatography (HPLC) purification treatment limits the improvement of production capacity, and subsequent alkalization treatment increases the difficulty of post-treatment, the operation is cumbersome, and it is easy to introduce impurities, which increases the difficulty of quality control.

This research group also studied the method reported in Chinese patent CN101360723: Compound 1 reacts with (R)-3-aminopiperidine dihydrochloride 2 in isopropanol and a small amount of water, using potassium carbonate as a base, at 60 °C without After less than 20 hours, the resulting mixture was added with acetonitrile, cooled to 25° C., filtered, the filter cake was washed with acetonitrile, and part of the filtrate was concentrated to obtain a solution of trilagliptin in acetonitrile. In this patent, neither the content of positional isomers nor the method for removing positional isomers is mentioned, and the reaction time is too long (not less than 20 hours), which is not conducive to industrial production; When it comes to isopropanol and acetonitrile, it increases the difficulty of solvent recovery and reuse. The research team conducted experiments according to this method, and the content of the positional isomer obtained by the reaction was greater than 0.6% (see Control Example 2); in the subsequent or further salt-forming (such as succinate) operation, the positional isomer was It will also form a salt with succinic acid, and then bring it into the finished product. The content of the position isomer salt impurities is 0.21%.

To sum up, the disclosed patents have the following problems:

1. The disclosed method does not conduct in-depth research on positional isomers, and does not reveal its influence on the quality of the final product;

2. The disclosed purification method (such as preparative HPLC purification) is difficult to realize industrialized production, reduces production efficiency, and limits the improvement of production capacity;

Therefore, there is an urgent need to find a process for preparing and purifying high-purity troxagliptin with higher yield and more suitable for industrial production.

SUMMARY OF THE INVENTION

In order to improve the deficiencies in the existing technology and obtain a high-yield preparation and purification process of high-purity troxagliptin that is more suitable for industrial production, this research group has deeply studied the preparation methods of troxagliptin reported in existing patents or literature. , using compound 1, ethanol and (R)-3-aminopiperidine dihydrochloride as starting materials to prepare trelagliptin, the state of the prepared trelagliptin is not studied in the disclosed preparation method: patent CN102140090 The mixture is directly prepared and purified by liquid phase to obtain the trifluoroacetate salt of trifluoroacetate; the acetonitrile solution of trilagliptin is obtained in the patent CN101360723. Only in the preparation of compound 34 in patent CN101360723, the preparation of troxagliptin by alkalization of troxagliptin hydrochloride is reported, wherein it is mentioned that troxagliptin is an off-white solid (see Comparative Example 3).

The research team was surprised to find in the experiment that the crude product of trelagliptin containing positional isomers can easily remove the positional isomers of trelagliptin by crystallization in water-miscible organic solvents, especially alcohols. The simultaneously obtained trelagliptin is in a crystalline form, and the crystalline form or the crystalline form is different from the crystalline form of the product prepared in Comparative Example 3 obtained by the method in the literature, and is a new crystalline form. See the table below for comparison:

The obtained new crystal form of Trelagliptin has high purity, and with it as a raw material, various salts (such as: Trelagliptin succinate, Trelagliptin hydrochloride, benzoic acid) can be easily synthesized. Trilagliptin), the product purity is as high as 99.8% or more, and the single impurity is less than 0.1%, which meets the strict purity standard of pharmaceutical raw materials. The yield is also higher, and this method has not been reported in literature or patents.

Accordingly, in one aspect, the present invention provides a novel crystal of high-purity troxagliptin; the crystal is also referred to as crystal form or crystal form.

The trelagliptin crystals provided by the present invention have characteristic peaks in the X-ray powder diffraction pattern (Cu Kα radiation) at the following 2 theta values: 4.8±0.2, 9.6±0.2, 18.4±0.2, 18.9±0.2

Further, the present invention provides a crystal of trelagliptin, whose X-ray powder diffraction pattern has characteristic peaks at the following 2 theta values: 4.8±0.2, 9.6±0.2, 13.9±0.2, 14.8±0.2°, 15.2±0.2, 18.4± 0.2, 18.9±0.2, 21.6±0.2, 26.7±0.2, 28.6±0.2

Further, the present invention provides trelagliptin crystals, whose X-ray powder diffraction pattern has characteristic peaks at the following 2 theta values: 4.8±0.2, 5.6±0.2, 9.6±0.2, 11.3±0.2, 12.5±0.2, 13.9±0.2 , 14.8±0.2°, 15.2±0.2, 16.8±0.2, 17.0±0.2, 18.4±0.2, 18.9±0.2, 19.4±0.2, 19.8±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 22.8±0.2, 26.7±0.2, 28.6±0.2

Further, the X-ray powder diffraction pattern of the trelagliptin crystal provided by the present invention is shown in FIG. 1 .

The trelagliptin crystal provided by the present invention has an endothermic peak near 168.32° C. in differential scanning calorimetry (DSC) analysis, as shown in FIG. 2 .

Those skilled in the art can understand that for qualitative or quantitative analysis of compounds such as X-ray powder diffraction patterns and differential scanning calorimetry analysis, under different detection conditions, these measured values are allowed to have certain values. difference.

On the other hand, the present invention provides the application of high-purity trelagliptin crystals in practice: the high-purity trelagliptin crystals obtained above are reacted with an acid to obtain high-purity trelagliptin salts, and these acids include organic acid and inorganic acid. Organic acids include, but are not limited to, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, and the like. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfate, nitric acid, and the like.

The high-purity trelagliptin salt obtained by the above-mentioned process is easy to operate, so it is suitable for large-scale industrial production. For example, the high-purity trelagliptin crystals obtained above are reacted with succinic acid to obtain high-purity trelagliptin succinate.

In another aspect, the preparation and purification crystallization process of high-purity troglitatin crystals provided by the present invention comprises the following steps:

Step 1: condensation reaction, namely compound 1 and (R)-3-aminopiperidine dihydrochloride 2 as raw materials, heating and refluxing in an organic solvent and in the presence of a base to undergo a condensation reaction to obtain a crude product of troxagliptin;

Step 2: recrystallization, that is, recrystallizing the crude trodagliptin obtained in step 1 in an organic solvent to obtain high-purity trodagliptin.

The above recrystallization process removes most of the position isomer impurities (compound 3) to obtain high-purity troxagliptin, and the position isomer impurities 3 are less than 0.1%.

Specifically, the condensation reaction of step 1 is to use compound 1 and (R)-3-aminopiperidine dihydrochloride 2 as raw materials, heat and reflux in an organic solvent and in the presence of a base to generate a condensation reaction, after the reaction is completed, filter and react The solid was precipitated by liquid cooling to obtain a crude product of the solid compound trilagliptin.

The organic solvent in the first step is an alcohol solvent, preferably ethanol and isopropanol.

The base in the step 1 is an organic base or an inorganic base, and the organic base is tri-n-butylamine, triethylamine, pyridine, etc.; the inorganic base is sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, etc.; preferably hydrogen carbonate Sodium, potassium bicarbonate and sodium carbonate.

The organic solvent in the second step is an alcohol solvent, preferably ethanol and isopropanol.

Compared with the original documents and patent reports, the present invention overcomes many deficiencies in the existing preparation methods and techniques of Trolagliptin: the yield is low, the purity is low, the operation is cumbersome, and it is not suitable for large-scale industrial production; The cost, high-yield, high-purity, and simple-to-operate new process for the preparation and purification of high-purity troxagliptin and troxagliptin salts has the following advantages:

1. Obtaining a new crystal of trelagliptin by crystallization in alcohol solution, the preparation is simple and convenient, and there is no need to prepare hydrochloride and then alkalize to obtain trelagliptin as in the comparative literature, and the production efficiency is greatly improved;

2. Using this new crystal of troxagliptin, the salt of troxagliptin can be conveniently prepared, with less impurities and meeting the medicinal standard;

3. The method for preparing the crystals of trelagliptin is simple and convenient, no special equipment is required, the positional isomers can be easily removed by crystallization, and the crystallization solvent is alcohol, which is environmentally friendly, easy to recover, and reusable.

The following abbreviations have the following meanings throughout the patent specification of the present invention: g (gram); mg (milligram); L (liter); mL (milliliter); M (molar concentration); mM (millimolar concentration); Hz (Hertz) ; MHz (megahertz); mmol (millimoles); mol (moles); min (minutes); h (hours); DCM (dichloromethane); DMF (N,N-dimethylformamide) DMSO (two Methyl sulfoxide); CuCN (cuprous cyanide); NBS (N-bromosuccinimide); AIBN (azobisisobutyronitrile); CCl ₄ (carbon tetrachloride); MgSO ₄ (magnesium sulfate) ).

Description of drawings

Fig. 1 is an X-ray powder diffraction pattern/XRPD pattern of a crystal of trelagliptin.

Fig. 2 is a differential scanning calorimetry/DSC chart of a crystal of Trolagliptin.

Fig. 3 is the X-ray powder diffraction pattern/XRPD pattern of the trilagliptin of Comparative Example 3

Detailed ways

The following will further illustrate the present invention through specific examples, which are not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and using instruments within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

In the following examples, unless otherwise specified, the test methods described are usually carried out under conventional conditions or conditions suggested by the manufacturer; the raw materials and reagents shown can be obtained by commercially available methods.

Synthesis of reference example, compound 1 (referring to Chinese patent CN102140090) :

Step 1. Preparation of 4-fluoro-2-methylbenzonitrile (Compound 4)

A mixture of 2-bromo-5-fluorotoluene (35 g, 185 mmol) and CuCN (20 g, 220 mmol) in DMF (500 mL) was refluxed for 24 h, the reaction was diluted with water and extracted with hexane, the organic phase was dried over _MgSO4 and the solvent was removed The product 4 was obtained (60% yield). ¹ H-NMR (400 MHz, CDC13): s 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

Step 2. Preparation of 2-Bromomethyl-4-fluorobenzonitrile (Compound 5)

A mixture of compound 4 (20 g, 148 mmol), NBS (26.4 g, 150 mmol) and AIBN (1 g) in CCl ₄ was refluxed for 2 h under nitrogen protection and the reaction was cooled to room temperature. The solids were removed by filtration and the organic solution was concentrated to give the crude product as an oil, which was used in the next step without further purification. ¹ H-NMR (400 MHz, CDC13): s 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

Step 3. Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (compound 1)

A mixture of 3-methyl-6-chlorouracil (12 g, 76 mmol), compound 5 (17.2 g, 80 mmol) and potassium carbonate (10 g, 80 mmol) in DMSO (100 mL) was stirred at 60° C. for 2 h, followed by water The reaction was diluted and extracted with ethyl acetate. The organic phase was dried with _MgSO4 and the solvent was removed. Purification by column chromatography gave product 1, 13.2 g (60% yield).

¹ H-NMR (400MHz, CDC13): δ.7.73 (dd, J=7.2, 8.4Hz, 1H), 7.26 (d, J-4.0Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd , J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H]294.

Synthesis of Comparative Example, Trolagliptin

Comparative example 1 (refer to the method of patent CN102140090)

Compound 1 (300 mg, 1.0 mmol), (R)-3-aminopiperidine dihydrochloride (266 mg, 1.225 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were dissolved in ethanol (3 ml) in a sealed tube at 100 °C ) and stirred for 2 hours, sampling HPLC detection, the positional isomer was 4.36%.

Comparative example 2 (refer to the method of patent CN101360723)

A mixture of compound 4 (1.2 g), IPA (10.8 ml), (R)-3-aminopiperidine dihydrochloride (0.7 g), pure water (0.08 ml) and potassium carbonate (2.5 g) was added at 60°C Heat until done. Then additional acetonitrile (3.6 ml) was added at 60°C and the mixture was allowed to cool to <25°C. The resulting final slurry was vacuum filtered and the filter cake was washed with acetonitrile (2 x 3.6 ml). The filtrate was concentrated in vacuo at 45°C to give 2.5 g of a solution of troxagliptin. By HPLC, the positional isomer was 0.64%.

This solution of troxagliptin was added to tetrahydrofuran (14.5ml) and isopropanol (5ml), the mixture was heated to 60°C, and the free base was completely dissolved. A solution of succinic acid in tetrahydrofuran (0.54g/8ml) was added dropwise, the dropping was completed, and the reaction was stirred at 60°C for 1 h. After the reaction was completed, the reaction was completed, stirred at room temperature, suction filtered, and the filter cake was dried with isopropanol (3ml×2) to obtain a solid tracker. Lipin succinate. The purity of trelagliptin succinate detected by HPLC was 99.42%, and the positional isomer was 0.21%.

Comparative example 3 (refer to the method of patent CN102140090)

Trolagliptin hydrochloride was prepared according to the method reported in the patent.

To a mixture of trilagliptin hydrochloride (2.0 g), dichloromethane (20 ml) and pure water (40 ml) was added 50% sodium hydroxide solution (2 ml) until the pH of the mixture was >12. The bidirectional mixture was stirred for 30 minutes and the organic layer was separated. The organic layer was extracted with dichloromethane (120 ml) and the combined organic layers were washed with pure water (200 ml). The organic layer was then concentrated in vacuo at 30°C for 3 hours to provide 1.5 g of Trolagliptin as a solid. The X-ray powder diffraction of this solid is shown in Figure 3:

Embodiment 1, the synthesis of compound Trilagliptin:

Compound 1 (10 g, 34 mmol), (R)-3-aminopiperidine dihydrochloride (8.0 g, 47 mmol) and sodium bicarbonate (13 g, 154 mmol) were stirred in ethanol (200 ml) at reflux for 3 hours; filtered while hot , the filter cake was washed with ethanol (50 ml), a large amount of solid was precipitated in the filtrate, and the filtrate was continuously stirred under an ice bath for 1 hour. The solid was filtered off, and the solid was recrystallized from ethanol to obtain 10 g of high-purity troxagliptin crystals (yield: 82.1%).

Embodiment 2, the synthesis of compound Trilagliptin:

Compound 4 (10 g, 34 mmol), (R)-3-aminopiperidine dihydrochloride (8.0 g, 4.7 mmol) and sodium bicarbonate (13 g, 154 mmol) were stirred in isopropanol (250 ml) at reflux for 2.5 hours; Filtration while hot, the filter cake was washed with isopropanol alcohol (50ml), the filtrate was stirred under ice bath for 1 hour, the solid was filtered out, and the solid was recrystallized with isopropanol to obtain 10.4 g of high-purity trelagliptin crystals (the yield was 10.4 g). 85.4%).

Embodiment 3, the synthesis of compound Trilagliptin:

Compound 4 (10 g, 34 mmol), (R)-3-aminopiperidine dihydrochloride (8.0 g, 47 mmol) and potassium bicarbonate (21 g, 152 mmol) were stirred in ethanol (200 ml) at reflux for 3.5 hours; filtered while hot , the filter cake was washed with ethanol (50ml), the filtrate was stirred in an ice bath for 1 hour, the solid was filtered out, and the solid was recrystallized with isopropanol to obtain 9.7g of high-purity troxagliptin crystals (yield 80.2%).

Embodiment 4, the synthesis of compound Trilagliptin:

Compound 4 (10 g, 34 mmol), (R)-3-aminopiperidine dihydrochloride (8.0 g, 47 mmol) and sodium carbonate (16 g, 151 mmol) were stirred in isopropanol (25 ml) at reflux for 2 hours; After filtration, the filter cake was washed with isopropanol (50 ml), and the filtrate was stirred under an ice bath for 1 hour. The solid was filtered off, and the solid was recrystallized from ethanol to obtain 10.2 g of high-purity troxagliptin crystals (yield: 84.1%).

Spectral data of the target product, ¹ H-NMR (400MHz, DMSO+D2O): δ.7.95-7.93 (dd, J=8.0, 8.0Hz, 1H), 7.36-7.32 (m, 1H), 7.19-7.16 (d , J=12.0Hz, 1H), 5.32(s, 1H), 5.17-5.08(m, 2H), 3.07(s, 3H), 3.04(s, 1H), 2.90-2.89(d, J=4Hz, 1H) ), 2.87(s, 1H), 2.60-2.55(t, J=8Hz, 12Hz, 1H), 2.45-2.40(t, J=8Hz, 12Hz, 1H), 1.81-1.78(m, 1H), 1.68- 1.64 (m, 1H), 1.46-1.37 (m, 1H), 1.19-1.17 (d, J=8Hz, 1H); MS (ES) [M+Na] 380.

The X-ray powder diffraction pattern/XRPD pattern of the trelagliptin crystal is shown in Figure 1;

The differential scanning calorimetry/DSC chart of the crystalline trelagliptin is shown in FIG. 2 .

HPLC analysis results are as follows:

HPLC detection Example 1 99.75%, positional isomer: 0.09% Example 2 99.79%, positional isomer: 0.08% Example 3 99.81%, positional isomer: 0.05% Example 4 99.70%, positional isomer: 0.10%

HPLC detection method:

Chromatographic column: Waters Symmetry C18 (250×4.6mm, 5um)

Mobile phase: A: 0.1% trifluoroacetic acid-water solution

B: acetonitrile

Column temperature: 30℃

Flow rate: 1.0ml/min

Detection wavelength: 278nm

Injection volume: 10ul

Gradient elution procedure:

time (min) Mobile phase A (%) Mobile phase B (%) 0 90 10 5 90 10 20 50 50 25 50 50 35 30 70 40 30 70 41 90 10 50 90 10

Embodiment 5, the preparation of succinic acid trilagliptin:

Trolagliptin (10 g) was suspended in tetrahydrofuran (100 ml) and isopropanol (35 ml), the mixture was heated to 60°C, and the free base was completely dissolved. A solution of succinic acid (3.75g) in tetrahydrofuran (3.75g/50ml) was added dropwise, the dropping was completed, the reaction was stirred at 60°C for 1 h, the reaction was completed, stirred at room temperature, filtered with suction, and the filter cake was dried with isopropanol (20ml×2) and dried in vacuo Trelagliptin succinate was obtained as a white solid. The purity of trelagliptin succinate detected by HPLC was 99.89%.

Embodiment 6, the preparation of Trolagliptin hydrochloride:

Trolagliptin (10 g) was suspended in tetrahydrofuran (100 ml) and isopropanol (35 ml), the mixture was heated to 60°C, and the free base was completely dissolved. Add dropwise a solution of 3mol/L hydrochloric acid in tetrahydrofuran (11ml), after the dropwise addition, stir for 1 h at 60°C. After the reaction is complete, stir at room temperature, filter with suction, use isopropanol (20ml×2) for the filter cake, and dry in vacuo to obtain a white solid koji Glycine hydrochloride. The purity of troxagliptin hydrochloride detected by HPLC was 99.85%.

Embodiment 7, the preparation of maleic acid trilagliptin:

Trolagliptin (10 g) was suspended in tetrahydrofuran (100 ml) and isopropanol (35 ml), the mixture was heated to 60°C, and the free base was completely dissolved. A solution of maleic acid (3.90g) in tetrahydrofuran (3.90g/50ml) was added dropwise, and the reaction was stirred at 60°C for 1 h. After the reaction was completed, the solution was stirred at room temperature, filtered with suction, and the filter cake was dried with isopropanol (20ml×2) under vacuum. Troxagliptin maleate was obtained as a white solid. The purity of troxagliptin maleate was 99.88% monitored by HPLC.

Claims (11)

1. A novel crystal of trelagliptin, the X-ray powder diffraction pattern (Cu Kα radiation) has characteristic peaks at the following 2 theta values: 4.8±0.2, 9.6±0.2, 18.4±0.2, 18.9±0.2. 2. according to claim 1, Trilagliptin is a crystalline body, and its X-ray powder diffraction pattern (Cu Kα radiation) also has characteristic peaks at following 2theta values: 4.8±0.2, 9.6±0.2, 13.9±0.2, 14.8±0.2° , 15.2±0.2, 18.4±0.2, 18.9±0.2, 21.6±0.2, 26.7±0.2, 28.6±0.2. 3. According to claim 1 or 2, trilagliptin is a crystal, and its differential scanning calorimetry (DSC) analysis has an endothermic peak around 168.32°C. 4. The use of the trelagliptin crystal of any one of claims 1-3 to react with an acid to obtain a high-purity trelagliptin salt. 5. purposes according to claim 4, is characterized in that, described acid is selected from succinic acid, maleic acid, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, Bisulfate, nitric acid. 6. The use according to claim 5, wherein the acid is selected from succinic acid. 7. a preparation and purification process of high-purity trilagliptin crystal, comprising the following steps:

Step 1: condensation reaction, namely compound 1 and (R)-3-aminopiperidine dihydrochloride 2 as raw materials, heating and refluxing in an organic solvent and in the presence of a base to undergo a condensation reaction to obtain a crude product of troxagliptin; Step 2: recrystallization, that is, recrystallizing the crude trodagliptin obtained in step 1 in an organic solvent to obtain high-purity trodagliptin. 8. The preparation and purification process according to claim 7, wherein the organic solvent in the step 1 is an alcohol solvent, preferably ethanol and isopropanol. 9. preparation and purification technique according to claim 7, is characterized in that, the alkali in described step 1 is to be selected from organic bases such as tri-n-butylamine, triethylamine or pyridine etc. or be selected from sodium bicarbonate, carbonic acid Inorganic bases of potassium, sodium carbonate or potassium bicarbonate. 10. The preparation and purification process according to claim 9, wherein the alkali in the step 1 is selected from sodium bicarbonate, potassium bicarbonate or sodium carbonate. 11. The preparation and purification process according to claim 7, wherein the organic solvent in the second step is an alcohol solvent, preferably ethanol and isopropanol.

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