CN111440145A

CN111440145A - Novel crystal form of high-purity trelagliptin and preparation method thereof

Info

Publication number: CN111440145A
Application number: CN202010294973.6A
Authority: CN
Inventors: 刘相奎; 陈武; 于净平; 胡宏亮; 朱雪焱; 袁哲东; 顾红梅; 王祥建
Original assignee: Shanghai Institute of Pharmaceutical Industry; Chia Tai Tianqing Pharmaceutical Group Co Ltd; China State Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry; Chia Tai Tianqing Pharmaceutical Group Co Ltd; China State Institute of Pharmaceutical Industry
Priority date: 2014-11-25
Filing date: 2014-11-25
Publication date: 2020-07-24
Also published as: CN105693691A

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

Novel crystal form of high-purity trelagliptin and preparation method thereof

The application is a divisional application of Chinese invention patent application (application date: 2014, 11, 25, application number: 201410692331.6; invention name: new crystal form of high-purity trelagliptin and preparation thereof).

Technical Field

The invention belongs to the field of chemical drug synthesis, and particularly relates to a novel high-purity crystal form of a hypoglycemic drug trelagliptin, and preparation and application thereof.

Background

Diabetes Mellitus (Diabetes mellitis, DM) is a metabolic disease of multiple etiologies, which is caused by elevated blood glucose due to absolute or relative insufficiency of insulin, causing metabolic disorders in the body, it can be classified into insulin-dependent Diabetes Mellitus (IDDM, also known as type I Diabetes) and non-insulin-dependent Diabetes Mellitus (non-insulin dependent Diabetes mellitis, NIDDM, also known as type II Diabetes), of which type II Diabetes is most common, accounting for over 90% of diabetic patients, dipeptidyl peptidase IV (IV) is a serine protease which is expressed in many tissues in vivo, such as intestine, liver, lung, kidney, etc., and T lymphocytes in the circulation, which is responsible for the metabolic cleavage of certain endogenous peptides (G L P-1(7-36), glucagon) in vivo, and which has been shown to be effective against various other peptides (GHRH, NPY, G4P-2, 8291-1, G-7-36) in vitro, as a selective inhibitor for the degradation of insulin-mediated by DPP-IV-7-IV-1-IV) in vivo, which is based on the finding that the physiological effects of the endogenous dipeptidyl peptidase IV-dependent Diabetes Mellitus (DPP) are highly effective in vivo, such as a selective inhibitor for the inhibition of the degradation of the growth of a human insulin-dependent Diabetes Mellitus (DPP-dependent Diabetes Mellitus, which is observed in vivo, which is mediated by the action of the endogenous DPP-dependent Diabetes Mellitus (DPP-dependent Diabetes Mellitus, which is expressed in many tissues in vivo, such as a mouse, which is expressed in vivo, such as a transient receptor-1-2-1-2-dependent Diabetes Mellitus, which is expressed in vivo, which is expressed in the secretion of the endogenous insulin-dependent Diabetes Mellitus, which is thought of various tissues in many tissues in mice, which is mediated by the secretion of the like, which is delayed, which is mediated by the secretion of the like, which is mediated by the secretion of the receptor, which is late-insulin.

Trelagliptin is a potent dipeptidyl peptidase IV (DPP-4) inhibitor developed by Wuta pharmaceutical industries, Japan, and controls blood glucose levels by selectively and persistently inhibiting DPP-4. The filing of a new drug application for trelagliptin is based on efficacy and safety data from several phase III clinical trials conducted in japanese type ii diabetic patients. The curative effect of trelagliptin is proved in all tests, and the trelagliptin has good safety and tolerance. The blood sugar level can be effectively controlled by once-weekly administration of trelagliptin, and the medication compliance of patients is expected to be improved. DPP-4 inhibitors are known to be a first group of novel type II diabetes drugs that can control blood glucose levels by improving the body's own ability, either as single drugs or in combination with other oral hypoglycemic agents. The medicine has unique action mechanism, has the unique advantages of no hypoglycemia, no weight increase, small side effect and the like, and has low incidence rate of adverse reaction of gastrointestinal tracts.

The chemical name of trelagliptin is 2- [ {6- [ (3R) -3-aminopiperidin-1-yl]-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl } methyl]-4-fluoro-benzonitrile; has a chemical formula of C₁₈H₂₀FN₅O₂.C₄H₆O₄(ii) a CAS number 865759-25-7.

The structural formula is as follows:

chinese patent CN102140090 discloses a method for preparing trelagliptin, which is shown as the following route:

in the operation process of the route, the compound 1, ethanol and (R) -3-aminopiperidine dihydrochloride 2 are added into a closed sealed tube, and nucleophilic substitution reaction is carried out at 100 ℃ to obtain the compound trelagliptin. Because the boiling point of the ethanol is only 78 ℃, the normal pressure heating can only reach the boiling point temperature, and the reaction temperature can be improved to a certain degree by being carried out in a sealed pipe; however, the pipe sealing operation is difficult to be applied to industrial production in large scale; in addition, because the 2-aminopiperidine structure simultaneously carries primary amine and secondary amine groups, the primary amine and the secondary amine groups can compete with the compound 1 to carry out substitution reaction to generate a positional isomer, namely a compound 3, which is shown as the following formula:

the research group carries out intensive research on the method disclosed by the patent CN102140090, according to the disclosed method, the content of the position isomer obtained after the reaction is more than 4.6 percent (see comparative example 1), the position isomer is generated in the reaction, and the purification treatment is needed, the method reported in the patent CN102140090 is to carry out the purification treatment by using a high performance liquid chromatography (HP L C) and further prepare the trogliptin trifluoroacetate, if the free base of the trogliptin needs to be prepared, the trogliptin trifluoroacetate needs to be salinized, and other salts (such as the succinic acid trogliptin) can be conveniently prepared from the obtained trogliptin free base.

The research group also studied the methods reported in chinese patent CN 101360723: reacting the compound 1 and (R) -3-aminopiperidine dihydrochloride 2 in isopropanol and a small amount of water by taking potassium carbonate as alkali at 60 ℃ for not less than 20 hours, adding acetonitrile into the obtained mixture, cooling to 25 ℃, filtering, washing a filter cake by the acetonitrile, and concentrating part of the filtrate to obtain an acetonitrile solution of trelagliptin. In this patent, neither the content of the positional isomer nor the method for removing the positional isomer is mentioned, and the reaction time is too long (not less than 20 hours), which is not suitable for industrial production; because of using isopropanol and acetonitrile, increased the difficulty of recovery and reuse of solvent. The group tested this way and the content of regioisomer obtained by the reaction was greater than 0.6% (see comparative example 2); in the subsequent or further salt-forming operation (for example, succinate salt formation), the position isomer is also salified with succinic acid and then brought into the finished product, and the impurity content of the position isomer salt is 0.21%.

In summary, the patents disclosed so far have the following problems:

1. the disclosed method does not carry out intensive studies on positional isomers and does not reveal their influence on the quality of the final product;

2. the disclosed purification method (such as purification for preparing HP L C) is difficult to realize industrial production, reduces the production efficiency and limits the improvement of the productivity;

therefore, the preparation and purification process of high-purity trelagliptin with higher yield and more suitability for industrial production is urgently needed to be found.

Disclosure of Invention

In order to improve the defects in the prior art and obtain a high-purity trelagliptin preparation and purification process with high yield and more suitability for industrial production, the research group intensively studies the trelagliptin preparation method reported in the prior patent or literature, and the state of the prepared trelagliptin is not studied in the published preparation method for preparing the trelagliptin by taking the compound 1, ethanol and (R) -3-aminopiperidine dihydrochloride as starting materials: in patent CN102140090, the mixture is directly prepared and liquid phase purified to obtain the trifluoroacetic acid salt of trelagliptin; the patent CN101360723 obtains acetonitrile solution of trelagliptin. Only in the preparation of compound 34 in patent CN101360723, the preparation of trelagliptin by basification of trelagliptin hydrochloride was reported, wherein it is mentioned that trelagliptin is an off-white solid (see comparative example 3).

The research group surprisingly finds out in experiments that the obtained crude trelagliptin product containing the position isomer is easily removed from the position isomer of the trelagliptin by crystallization in an organic solvent which is miscible with water, particularly alcohol, and the obtained trelagliptin is in a crystal form, wherein the crystal form or the crystal form of the obtained crude trelagliptin product is different from that of a product prepared in a reference example 3 obtained according to a literature method and is a new crystal form. The comparison is shown in the following table:

the obtained new crystal form of the trelagliptin has high purity, various salts (such as trelagliptin succinate, trelagliptin hydrochloride and trelagliptin benzoate) of the trelagliptin can be easily synthesized and prepared by taking the new crystal form as a raw material, the product purity is up to more than 99.8 percent, and the single impurity is less than 0.1 percent, so that the strict purity standard of medicinal raw material medicines is achieved. The yield is also higher, and the method is not reported in the literature or patents.

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

The trogliptin crystal provided by the invention has characteristic peaks in an X-ray powder diffraction pattern (Cu K α radiation) at the following 2theta values of 4.8 +/-0.2, 9.6 +/-0.2, 18.4 +/-0.2 and 18.9 +/-0.2

Further, the invention provides a crystalline body of Trelagliptin, which has an X-ray powder diffraction pattern with characteristic peaks at the following 2theta values: 4.8 +/-0.2, 9.6 +/-0.2, 13.9 +/-0.2, 14.8 +/-0.2 degrees, 15.2 +/-0.2, 18.4 +/-0.2, 18.9 +/-0.2, 21.6 +/-0.2, 26.7 +/-0.2 and 28.6 +/-0.2

Further, the invention provides a crystalline body of Trelagliptin, which has an X-ray powder diffraction pattern with characteristic peaks at the following 2theta 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 crystalline trelagliptin provided by the invention is shown in fig. 1.

The Differential Scanning Calorimetry (DSC) analysis of the trelagliptin crystal provided by the invention has an endothermic peak near 168.32 ℃, as shown in figure 2.

It will be appreciated by those skilled in the art that for compounds having X-ray powder diffraction patterns and differential scanning calorimetry analysis etc. patterns for qualitative or quantitative analysis, the measurements will allow for some variation in different detection conditions.

On the other hand, the invention provides the application of the high-purity trelagliptin crystal in the practice: the high-purity trogliptin crystal obtained by the method reacts with acid to obtain high-purity trogliptin salt, and the acid comprises 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 salts, nitric acid, and the like.

The high-purity trelagliptin salt obtained by the process is simple and convenient to operate, so that the method is suitable for large-scale industrial production. For example, the high-purity trogliptin crystal obtained in the above way reacts with succinic acid to obtain high-purity trogliptin succinate.

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

the method comprises the following steps: performing condensation reaction, namely heating and refluxing a compound 1 and (R) -3-aminopiperidine dihydrochloride 2 serving as raw materials in an organic solvent in the presence of alkali to perform condensation reaction to obtain a crude trelagliptin product;

step two: and (4) recrystallizing, namely recrystallizing the crude trelagliptin product obtained in the step one in an organic solvent to obtain high-purity trelagliptin.

The recrystallization process removes most of the regioisomer impurity (compound 3) to obtain high-purity trelagliptin, and the regioisomer impurity 3 is less than 0.1%.

Specifically, the condensation reaction in the first step is to take the compound 1 and the (R) -3-aminopiperidine dihydrochloride 2 as raw materials, heat reflux the raw materials in an organic solvent and in the presence of alkali to carry out condensation reaction, filter the reaction solution after the reaction is finished, and cool the reaction solution to separate out a solid, thereby obtaining a crude product of the solid compound trogliptin.

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

The base in the step one is organic base or inorganic base, and the organic base is tri-n-butylamine, triethylamine, pyridine and the like; the inorganic base is sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, etc.; sodium bicarbonate, potassium bicarbonate and sodium carbonate are preferred.

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

Compared with the original documents and patent reports, the invention overcomes the defects of the existing preparation method and process of trelagliptin: the yield is low, the purity is low, the operation is complicated, and the method is not suitable for large-scale industrial production; further provides a novel preparation and purification process of high-purity trelagliptin and trelagliptin salt, which has the advantages of low cost, high yield, high purity and simple and convenient operation, and has the following advantages:

1. the novel trogliptin crystal is obtained by crystallization in an alcoholic solution, the preparation is simple and convenient, the trogliptin crystal does not need to be prepared into hydrochloride and then alkalized to obtain the trogliptin in an image contrast document, and the production efficiency is greatly improved;

2. the novel crystal of the trelagliptin can be used for conveniently preparing the trelagliptin salt, has few impurities and reaches the medicinal standard;

3. the method for preparing the trelagliptin crystal is simple and convenient, special equipment is not needed, the position isomer can be easily removed through crystallization, and the crystallization solvent is alcohol, so that the method is environment-friendly, easy to recover and capable of being repeatedly used.

The following abbreviations have the following meanings throughout the present patent specification, g (g), mg (mg), L (L), M L (mL), M (molarity), mM (millimolar), Hz (Hertz), MHz (megahertz), mmol (millimolar), mol (mol), min (min), h (h), DCM (dichloromethane), DMF (N, N-dimethylformamide) DMSO (dimethyl sulfoxide), CuCN (cuprous cyanide), NBS (N-bromosuccinimide), AIBN (azobisisobutyronitrile), CCl (CCl)₄(carbon tetrachloride); MgSO (MgSO)₄(magnesium sulfate).

Drawings

Figure 1 is an X-ray powder diffraction pattern/XRPD pattern of crystalline Trelagliptin.

Figure 2 is a differential scanning calorimetry/DSC plot of crystalline Trelagliptin.

FIG. 3 is an X-ray powder diffraction pattern/XRPD pattern of trelagliptin of comparative example 3

Detailed Description

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the protection scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

In the examples below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the figure can be obtained by a commercially available mode.

Reference example, Synthesis of Compound 1 (see Chinese patent CN102140090)：

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

A mixture of 2-bromo-5-fluorotoluene (35g, 185mmol) and CuCN (20g, 220mmol) in DMF (500m L) was refluxed for 24 hours, diluted with water and extracted with hexane, MgSO₄The organic phase was dried and the solvent was removed to give product 4 (yield 60%).¹H-NMR(400MHz，CDC13)：s 7.60(dd，J＝5.6，8.8Hz，1H)，6.93-7.06(m，2H)，2.55(s，3H)。

Step 2. preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound 5)

Compound 4(20g, 148mmol), NBS (26.4g, 150mmol) and AIBN (1g) in CCl under nitrogen blanket₄The mixture in (1) was refluxed for 2 hours and the reaction was cooled to room temperature. The solid was 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.¹H-NMR(400MHz，CDC13):s 7.68(dd，J＝5.2，8.4Hz，1H)，7.28(dd，J＝2.4,8.8Hz，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 (12g,76mmol), compound 5(17.2g,80mmol) and potassium carbonate (10g, 80mmol) in DMSO (100m L) was stirred at 60 ℃ for 2h, the reaction was diluted with water and extracted with ethyl acetate MgSO₄The organic phase was dried and the solvent was removed. Purification by column chromatography gave 1, 13.2g (60% yield).

¹H-NMR(400MHz，CDC13):.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＝2.0,9.0Hz，1H)，6.034(s，2H)，3.39(s，3H)。MS(ES)[m+H]294。

Comparative example, Synthesis of Trelagliptin

Comparative example 1 (see patent CN102140090 method)

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

Comparative example 2 (see patent CN101360723 method)

A mixture of compound 4(1.2g), IPA (10.8ml), (R) -3-aminopiperidine dihydrochloride (0.7g), pure water (0.08ml) and potassium carbonate (2.5g) was heated at 60 ℃ until completion then acetonitrile (3.6ml) was added at 60 ℃ and the mixture was allowed to cool to <25 ℃.

Adding the trelagliptin solution into tetrahydrofuran (14.5ml) and isopropanol (5ml), heating the mixture to 60 ℃, completely dissolving free alkali, dropwise adding succinic acid tetrahydrofuran (0.54g/8ml) solution, stirring and reacting at 60 ℃ for 1h after the dropwise adding is finished, stirring at room temperature, performing suction filtration, using isopropanol (3mlx2) to prepare a filter cake, and performing vacuum drying to obtain solid trelagliptin succinate, wherein the purity of the trelagliptin succinate is 99.42% and the positional isomer is 0.21% by HP L C detection.

Comparative example 3 (see patent CN102140090 method)

Trelagliptin hydrochloride was prepared according to the patent reported method.

To a mixture of trelagliptin hydrochloride (2.0g), dichloromethane (20ml) and pure water (40ml) was added 50% sodium hydroxide solution (2ml) 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 (120ml) and the combined organic layers were washed with pure water (200 ml). The organic layer was then concentrated in vacuo at 30 ℃ for 3 hours to provide 1.5g of trelagliptin in solid form. The X-ray powder diffraction of this solid is shown in figure 3:

example 1 synthesis of the compound trelagliptin:

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

Example 2 synthesis of the compound trelagliptin:

compound 4(10g, 34mmol), (R) -3-aminopiperidine dihydrochloride (8.0g, 4.7mmol) and sodium bicarbonate (13g, 154mmol) were stirred at reflux in isopropanol (250ml) for 2.5 h; filtering while hot, washing the filter cake with isopropanol alcohol (50ml), stirring the filtrate for 1 hour in ice bath, filtering out solid, and recrystallizing the solid with isopropanol to obtain high-purity trelagliptin crystal 10.4g (yield 85.4%).

Example 3 synthesis of the compound trelagliptin:

compound 4(10g, 34mmol), (R) -3-aminopiperidine dihydrochloride (8.0g,47mmol) and potassium hydrogencarbonate (21g, 152mmol) were stirred at reflux in ethanol (200ml) for 3.5 hours; filtering while hot, washing filter cake with ethanol (50ml), stirring the filtrate for 1 hour in ice bath, filtering out solid, and recrystallizing the solid with isopropanol to obtain high-purity trelagliptin crystal 9.7g (yield 80.2%).

Example 4 synthesis of the compound trelagliptin:

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

The map data of the target product is obtained,¹H-NMR(400MHz,DMSO+D2O):.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;

a differential scanning calorimetry/DSC diagram of crystalline trelagliptin is shown in figure 2.

The HP L C analysis results were as follows:

	HP L C assay
		Example 1	99.75%, positional isomer: 0.09 percent
Example 2	99.79%, positional isomer: 0.08 percent
		Example 3	99.81%, positional isomer: 0.05 percent
Example 4	99.70%, positional isomer: 0.10 percent

HP L C detection method:

chromatographic column Waters Symmetry C18(250 × 4.6.6 mm, 5um)

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

B: acetonitrile

Column temperature: 30 deg.C

Flow rate: 1.0ml/min

Detection wavelength: 278nm

Sample introduction volume: 10ul of

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

Example 5 preparation of trelagliptin succinate:

suspending trelagliptin (10g) in tetrahydrofuran (100ml) and isopropanol (35ml), heating the mixture to 60 ℃, completely dissolving free alkali, dropwise adding a tetrahydrofuran (3.75g/50ml) solution of succinic acid (3.75g), stirring at 60 ℃ for reacting for 1h after dropwise adding, stirring at room temperature after the reaction is finished, performing suction filtration, using isopropanol (20mlx2) to obtain a filter cake, and performing vacuum drying to obtain white solid trelagliptin succinate, wherein the purity of the trelagliptin succinate is 99.89% by HP L C detection.

Example 6 preparation of trelagliptin hydrochloride:

suspending trelagliptin (10g) in tetrahydrofuran (100ml) and isopropanol (35ml), heating the mixture to 60 ℃, completely dissolving free alkali, dropwise adding a tetrahydrofuran solution (11ml) of 3 mol/L hydrochloric acid, stirring and reacting at 60 ℃ for 1h after dropwise adding, stirring and filtering at room temperature after the reaction is finished, and performing vacuum drying on a filter cake by using isopropanol (20mlx2) to obtain white solid trelagliptin hydrochloride, wherein the purity of the trelagliptin hydrochloride is 99.85% by HP L C detection.

Example 7 preparation of trelagliptin maleate:

suspending trelagliptin (10g) in tetrahydrofuran (100ml) and isopropanol (35ml), heating the mixture to 60 ℃, completely dissolving free alkali, dripping a tetrahydrofuran (3.90g/50ml) solution of maleic acid (3.90g), stirring and reacting at 60 ℃ for 1h, stirring and filtering at room temperature after the reaction is finished, vacuum-drying a filter cake by using isopropanol (20mlx2) to obtain white solid trelagliptin maleate, and monitoring the purity of the trelagliptin maleate to be 99.88% by using HP L C.

Claims

1. The X-ray powder diffraction pattern (Cu K α radiation) of the crystal of the new Trelagliptin has characteristic peaks at the following 2theta values of 4.8 +/-0.2, 9.6 +/-0.2, 18.4 +/-0.2 and 18.9 +/-0.2.

2. According to claim 1, trelagliptin is crystalline and has an X-ray powder diffraction pattern (Cu K α radiation) with characteristic peaks at 2theta values of 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 and 28.6 + -0.2.

3. According to claim 1 or 2, trelagliptin is crystalline and has an endothermic peak near 168.32 ℃ in Differential Scanning Calorimetry (DSC) analysis.

4. Use of the crystalline Trelagliptin according to any of claims 1 to 3 for the reaction with an acid to obtain a Trelagliptin salt of high purity.

5. Use according to claim 4, characterized in that the acid is selected from succinic acid, maleic acid, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen sulfate, nitric acid.

6. Use according to claim 5, characterized in that the acid is selected from succinic acid.

7. A preparation and purification process of high-purity trelagliptin crystals comprises the following steps:

8. The process according to claim 7, wherein the organic solvent in step one is an alcohol solvent, preferably ethanol or isopropanol.

9. The production and purification process according to claim 7, wherein the base in the first step is an organic base selected from tri-n-butylamine, triethylamine, pyridine, etc., or an inorganic base selected from sodium bicarbonate, potassium carbonate, sodium carbonate, or potassium bicarbonate.

10. The process according to claim 9, wherein the base in step one is selected from sodium bicarbonate, potassium bicarbonate or sodium carbonate.

11. The process according to claim 7, wherein the organic solvent in step two is an alcohol solvent, preferably ethanol or isopropanol.