Pharmaceutical Intermediates

Abstract

The present invention relates to a semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate and methods for preparing this compound.

Description

[Technical Field]

[0001] The present invention relates to a method for producing pharmaceutical intermediates, specifically (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate and (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0002] The present invention also relates to the preparation of 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione (linagliptin) or a salt thereof using (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate. [Background technology]

[0003] Linagliptin is named 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione and has the following structure: [ka]

[0004] Linagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor and is classified as an oral hypoglycemic agent.

[0005] Linagliptin is marketed in many countries as Trajenta®, an oral hypoglycemic agent. Linagliptin is indicated for the treatment of type 2 diabetes mellitus as monotherapy and as an adjunct to diet and exercise to improve glycemic control. Linagliptin is also indicated for the treatment of type 2 diabetes mellitus in combination with empagliflozon (Glyxambi®) and in combination with metformin (Jentadueto®).

[0006] Linagliptin can be prepared according to the procedures described in International Publication No. WO2004018468 and International Publication No. WO2014097314.

[0007] The process typically begins with the base-mediated condensation of a chloride compound (compound (I)) with a xanthine compound (compound (II)) to give compound (III).

[0008] In the next step, the method involves a second base-mediated condensation of compound (III) with (R)-3-(Boc-amino)piperidine to give compound (V).

[0009] The tert-butyloxycarbonyl (Boc) protecting group is then removed to give the desired compound, linagliptin. [ka]

[0010] This method is well established in the art.

[0011] However, although this method can obtain linagliptin with acceptable yield and purity, it requires the separation of multiple intermediates before isolating the final product. Moreover, the methods described so far in the prior art generally cannot completely remove impurities, and some colored impurities usually remain in the final product. Therefore, most commercially available linagliptin is not completely white, but has a slightly yellowish tint.

[0012] Therefore, further optimization of this method is desirable.

[0013] In fact, both large-scale chemical synthesis and purification are the subject of constant study and optimization by those skilled in the art. Due to economies of scale, small improvements in certain reaction or purification parameters are particularly economically significant. Therefore, optimizing large-scale synthesis or purification, for example, to increase chemical yield, reduce stepwise operations, shorten reaction time, lower reaction temperature, reduce the amount of catalyst or solvent used, increase reagent desirability, reduce by-product formation, more environmentally friendly synthesis, or improve chemical purity, is important for both chemical manufacturers and suppliers.

[0014] Additionally, process optimizations that reduce the need for multiple or laborious purifications are particularly beneficial. Shortening synthetic procedures (where two or more previously independent synthetic transformations converge into a "single" method, thus requiring only one purification step), or "one-pot" transformations, or identification of intermediates for recrystallization, or precipitation, or removal of impurities by conversion to a fugitive intermediate, or substitution with cheaper, greener, or less toxic reagents, are attractive and economically desirable goals.

[0015] However, achieving improvement in practice is not easy.

[0016] For example, "one-pot" transformations (ie, reactions in which reactants undergo sequential chemical reactions (multi-step synthesis) in a single reaction vessel) are an attractive solution.

[0017] However, in practice, if intermediates are not separated in one-pot processes, intermediate by-products usually accumulate, adversely affecting the product yield. Furthermore, intermediate by-products that are structurally close to the target compound are often difficult to separate, which adversely affects the purity of the product.

[0018] Typically, removal of intermediate by-products requires expensive and time-consuming purification procedures, such as the use of high performance liquid chromatography (HPLC), but such procedures are not economically viable for large-scale transformations requiring many kilograms of the target compound.

[0019] In view of these challenges, various methods have been proposed to optimize the production of linagliptin.

[0020] One such method focuses on manipulating the polymorphic form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound (V)) as a means to selectively isolate a key intermediate for linagliptin and simultaneously remove impurities.

[0021] For example, Compound V is obtained as a highly pure amorphous intermediate in International Publication WO2014097314 without the need for column chromatography. Similarly, Compound V is obtained as a crystalline intermediate in International Publication WO2019064214, again without the need for column chromatography.

[0022] However, the procedures described in International Publication WO2014097314 and International Publication WO2019064214 have various drawbacks.

[0023] First, although various polymorphs of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)carbamate can be obtained without the need for column chromatography, the purity is not optimal.

[0024] Second, these methods do not provide a one-pot solution, as they require the isolation of multiple intermediates before isolating the final product.

[0025] A further drawback is that the manufacturing strategies and solid forms disclosed in the prior art provide (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)carbamate in a form that is difficult, impractical, or impossible to filter, especially on a multi-kilogram manufacturing scale.

[0026] As a result, since (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is a key intermediate for providing linagliptin, it is highly desirable to provide a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in increased purity and / or yield using a simplified synthesis.

[0027] Ideally, the solid form reduces or prevents the presence of impurities in the final linagliptin product, such as Compounds (I) through (IV) and their by-products, as well as other impurities generated during synthesis.

[0028] It would also be desirable to provide (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in solid form with increased purity and yield through simplified synthetic procedures. It would also be desirable to provide a solid form that is not only easy to handle but also easy to isolate, e.g., easy or practical to filter.

[0029] Therefore, there remains a need in the art for improved solid forms of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate. Summary of the Invention

[0030] Accordingly, the present invention provides a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0031] The inventors have identified this solid form as quasi-amorphous because it exhibits long-range order and crystalline structure unlike materials that are considered to be in a completely amorphous state, but at the same time, the material does not possess all of the properties of a crystalline solid.

[0032] For example, the quasi-amorphous form of the present invention exhibits broad peaks (as opposed to sharp peaks) in its X-ray powder diffraction spectrum (XRPD) (see Figure 1).

[0033] Furthermore, differential scanning calorimetry (DSC) thermograms show a long melting endotherm followed by a single sharp melting peak (see Figure 2).

[0034] Pure crystalline materials exhibit a single sharp peak; similarly, pure amorphous substances melt over a range with no specific end point, with endotherms slowly appearing and disappearing.

[0035] However, the quasi-amorphous form exhibits a DSC thermogram with both crystalline and amorphous characteristics, as can be seen in Figure 2. In particular, the longer endotherm indicates that the amorphous phase begins to melt first, followed by the crystalline phase, with a sharp peak.

[0036] The DSC thermograms in Figures 5 to 8 also show that the quasi-amorphous material has both crystalline and amorphous properties.

[0037] As noted above, the quasi-amorphous forms of the present invention exhibit broad peaks (as opposed to sharp peaks) in an X-ray powder diffraction spectrum (XRPD). Thus, the XRPD peaks can be defined either by reference to the sharp point at the apex of each broad peak, or by reference to the width of each peak calculated at its base.

[0038] Thus, the present invention also provides a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, characterized by XRPD peaks at 2θ (°) ±0.2°: 3.0, 10.3, 15.3, 18.8, 21.4, and 26.5.

[0039] Characterizing peaks, including peaks of lower relative intensity, are as follows: XRPD 2θ(°)±0.2°: 3.0, 7.1, 8.9, 10.3, 12.7, 15.3, 16.8, 18.8, 21.4, 24.3 and 26.5.

[0040] The present invention also provides a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate characterized by broad XRPD peaks, with widths of each peak at the base of the respective peaks, in degrees 2θ±0.2°: 2.3-4.0, 9.7-10.7, 14.8-15.8, 20.5-22.5, and 25.8-27.5.

[0041] For the avoidance of any doubt, the width of each peak is calculated at the base of each peak by reading its respective 2θ (°)±0.2° value at the point where the upslope of the peak begins from the x-axis and at the point where the downslope of the peak intersects the x-axis of the XRPD.

[0042] In one embodiment, the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is further characterized by a differential scanning calorimetry (DSC) thermogram with a melting onset of 144-146°C, a melting end of 156-158°C, and a melting peak of 154-156°C.

[0043] In particular, the quasi-amorphous form is further characterized by a differential scanning calorimetry (DSC) thermogram with an onset of melting between 144-146°C, an end of melting between 156-158°C, and a melting peak between 154.5-155.5°C.

[0044] In particular, the quasi-amorphous form is further characterized by a differential scanning calorimetry (DSC) thermogram with an onset of melting between 144.0 and 146.0°C, an end of melting between 156.0 and 158.0°C, and a melting peak between 154.5 and 155.5°C when the heating rate of the DSC instrument is 2.5°C / min.

[0045] The quasi-amorphous form is further characterized by a differential scanning calorimetry (DSC) thermogram with an onset of melting between 147.0 and 149.0°C, an end of melting between 155.5 and 157.5°C, and a melting peak between 154.0 and 155.0°C when the heating rate of the DSC instrument is 1°C / min.

[0046] The quasi-amorphous form is further characterized by a differential scanning calorimetry (DSC) thermogram with an onset of melting between 147.0 and 149.0°C, an end of melting between 156.0 and 158.0°C, and a melting peak between 154.0 and 155.0°C when the heating rate of the DSC instrument is 2°C / min.

[0047] The quasi-amorphous form is further characterized by a differential scanning calorimetry (DSC) thermogram with an onset of melting between 144.0 and 146.0°C, an end of melting between 156 and 158°C, and a melting peak between 154.5 and 155.5°C when the heating rate of the DSC instrument is 5°C / min.

[0048] The quasi-amorphous form is further characterized by a differential scanning calorimetry (DSC) thermogram with an onset of melting between 143.5 and 145.5°C, an end of melting between 157.5 and 159.5°C, and a melting peak between 155.5 and 156.5°C when the heating rate of the DSC instrument is 10°C / min.

[0049] In one embodiment, the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is characterized by the XRPD in FIG. 1.

[0050] In one embodiment, the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is characterized by the XRPD of FIG. 2.

[0051] In one embodiment, the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is characterized by any one of the DSC thermograms in Figures 5-8.

[0052] The semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate of the present invention is also characterized by the following characteristic peaks: IR(cm -1 ):596, 761, 954, 1054, 1129, 1167, 1245, 1288, 1311, 1365, 1401, 1439, 1515, 1569, 1621, 1664, 1701, 2942 and 3334.

[0053] In one embodiment, the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is characterized by the IR spectrum of FIG.

[0054] As noted above, the inventors have identified the solid forms of the present invention as quasi-amorphous because they exhibit long-range order and crystalline structure, unlike materials that are considered to be in a completely amorphous state, but at the same time do not possess all the properties of a crystalline solid, i.e., the solid forms of the present invention have crystalline and amorphous properties.

[0055] In one embodiment, the semi-amorphous form is further characterized by a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, having a crystallinity of 25% to 75%.

[0056] In one embodiment, the present invention provides a semi-amorphous or solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate characterized by a crystallinity of 25% to 75%.

[0057] The present invention also provides a process for the preparation of a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, comprising: (i) dissolving (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in dichloromethane to form a solution; (ii) adding methyl tert-butyl ether to the solution; and (iii) recovering the resulting precipitate from said solution. The method comprises:

[0058] This method was found to provide a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in high yield and purity without the need for column chromatography.

[0059] This method has been found to produce a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate that is virtually colorless. That is, this method provides the compound as a pure white solid or a pure off-white solid while maintaining a high chemical yield of the product.

[0060] This method has also been found to provide a solid form with improved filterability compared to solid forms provided by prior art methods. [Brief explanation of the drawings]

[0061] The present invention will now be described with reference to the accompanying drawings. [Figure 1] FIG. 1 shows the XRPD spectrum of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (product of Example 2). [Figure 2]FIG. 2 shows a DSC trace of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (the product of Example 2). [Figure 3] FIG. 3 shows an IR trace of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (product of Example 2). [Figure 4] FIG. 4 shows a microscope image of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate. [Figure 5] FIG. 5 shows a DSC trace of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (the product of Example 2) when the heating rate of the DSC instrument was 1° C. / min. [Figure 6] FIG. 6 shows a DSC trace of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (the product of Example 2) when the heating rate of the DSC instrument was 2° C. / min. [Figure 7]FIG. 7 shows a DSC trace of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (the product of Example 2) when the heating rate of the DSC instrument was 5° C. / min. [Figure 8] FIG. 8 shows a DSC trace of the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (the product of Example 2) when the heating rate of the DSC instrument was 10° C. / min. Specific Description of the Invention

[0062] In step (i) of the process, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is dissolved in dichloromethane to form a solution.

[0063] In one embodiment, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is dissolved in dichloromethane to form a solution, activated carbon is added to the solution to form a suspension, and the resulting suspension is stirred.

[0064] In one embodiment, in addition to activated carbon, magnesium sulfate may also be added to the dichloromethane solution.

[0065] The suspension is stirred for 1 to 3 hours, preferably for 2 hours.

[0066] Preferably, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is dissolved in dichloromethane to form a solution, activated carbon and magnesium sulfate are added to the solution, and the resulting mixture is stirred for 1 hour to 3 hours, preferably 2 hours, prior to step (ii).

[0067] If activated carbon or activated carbon and magnesium sulfate have been added to the dichloromethane solution, they are removed prior to step (ii). The activated carbon and magnesium sulfate are typically removed by filtration. Alkaline activated carbon is preferred.

[0068] The dichloromethane solution formed in step (i), typically the solution obtained after removing the activated carbon and magnesium sulfate, is heated to 20°C to 40°C, preferably 25°C to 38°C, prior to the addition of methyl tert-butyl ether in step (ii). Alternatively, the solution is heated to 35°C to 40°C prior to the addition of methyl tert-butyl ether in step (ii).

[0069] Preferably, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is dissolved in dichloromethane to form a solution, activated carbon and magnesium sulfate are added to the solution, and the resulting mixture is stirred for 1 hour to 3 hours, preferably 2 hours. Thereafter, the activated carbon and magnesium sulfate are removed from the solution, and the solution is heated to 20°C to 40°C, preferably 25°C to 38°C, prior to the addition of methyl tert-butyl ether in step (ii). Alternatively, the solution is heated to 35°C to 40°C prior to the addition of methyl tert-butyl ether in step (ii).

[0070] In one embodiment, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is dissolved in dichloromethane to form a solution, and the resulting solution is heated to 20° C. to 40° C., preferably 25° C. to 38° C., and more preferably 34° C. to 36° C., prior to the addition of methyl tert-butyl ether in step (ii). Alternatively, the solution is heated to 35° C. to 40° C. prior to the addition of methyl tert-butyl ether in step (ii).

[0071] The amount of dichloromethane used in step (i) is not critical and typically ranges from about 1.5 mL to about 10 mL of dichloromethane per mg of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, and preferably ranges from about 2 mL to about 5 mL of dichloromethane per mg of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0072] In step (ii) of the process, methyl tert-butyl ether is added to the dichloromethane solution and the resulting mixture is stirred.

[0073] Preferably, methyl tert-butyl ether is added dropwise to the dichloromethane solution for 10 minutes to 2 hours, preferably 1 hour.

[0074] Methyl tert-butyl ether is typically added so that, upon completion of the addition of methyl tert-butyl ether, the volume ratio of dichloromethane to methyl tert-butyl ether is 1:1 to 1:10. Preferably, the volume ratio is 1:2 to 1:8. Even more preferably, the volume ratio is 1:3 to 1:6, such as 1:4, or such as 1:4.5.

[0075] In one embodiment, once the addition of methyl tert-butyl ether to the dichloromethane solution is complete, the resulting mixture is cooled, optionally with stirring, to between 0° C. and 10° C., preferably 5° C., preferably at a cooling rate of −10° C. / hour. Cooling generally further improves the final yield and / or purity of the resulting solid form of the (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate final product.

[0076] After cooling, the mixture is stirred for 1 to 3 hours, preferably 2 hours.

[0077] In one embodiment, in step (i) of the process, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is dissolved in dichloromethane to form a solution, and the solution is heated to between 20° C. and 40° C., preferably between 25° C. and 38° C., more preferably between 34° C. and 36° C., and in step (ii) of the process, methyl tert-butyl ether is then added dropwise to the dichloromethane solution, and upon complete addition of the methyl tert-butyl ether, the resulting mixture is cooled between 0° C. and 10° C., preferably at 5° C., preferably at a cooling rate of −10° C. / hour.

[0078] Preferably, activated carbon is added to the solution and the mixture is stirred for 1 hour to 3 hours, preferably 2 hours, after which the activated carbon is removed by filtration prior to step (ii). Alkaline activated carbon is preferred.

[0079] Preferably, methyl tert-butyl ether is added such that, typically when the addition of methyl tert-butyl ether is complete, the volume ratio of dichloromethane to methyl tert-butyl ether is 1:3 to 1:6, such as 1:4, or such as 1:4.5.

[0080] After adding methyl tert-butyl ether or cooling the resulting mixture, if carried out, the mixture is usually stirred for a certain period of time. Stirring can usually be continued for up to 72 hours, preferably up to 48 hours, more preferably up to 24 hours, even more preferably up to 12 hours, even more preferably up to 6 hours, and even more preferably up to 3 hours. The preferred stirring time is 1 to 3 hours, preferably 2 hours.

[0081] In step (iii) of the process, the resulting precipitate, i.e., a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, is recovered from the mixture, preferably by gravity filtration or vacuum filtration.

[0082] In one embodiment, a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is collected from the mixture at a temperature between 0° C. and 25° C.

[0083] To isolate the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, the collected precipitate is washed with a mixture of dichloromethane and methyl tert-butyl ether (usually 1:4 dichloromethane:methyl tert-butyl ether).

[0084] Before isolating the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, the collected precipitate is washed with a mixture of dichloromethane and methyl tert-butyl ether (usually 1:4 dichloromethane:methyl tert-butyl ether or 1:4.5 dichloromethane:methyl tert-butyl ether). For example, the solid form is added to a mixture of dichloromethane and methyl tert-butyl ether in a volume ratio of 1:3 to 1:6, for example, 1:4, or for example, 1:4.5, and stirred for 1 to 3 hours, preferably 2 hours. The solid form is then again collected by filtration, for example, by gravity filtration or vacuum filtration.

[0085] The solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is then dried to give a highly pure white solid.

[0086] Preferably, the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by the process described hereinabove is a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0087] The quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by the present method is defined and characterized as above.

[0088] In one embodiment, a process for preparing a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate comprises: (i) dissolving (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in dichloromethane to form a solution; (ii) adding methyl tert-butyl ether to said solution; (iii) recovering the resulting precipitate from the solution, for example by filtration; (iv) adding the recovered product to dichloromethane and methyl tert-butyl ether, and optionally stirring the resulting mixture; and (v) recovering the product from the dichloromethane and methyl tert-butyl ether. The compound comprises:

[0089] Prior to carrying out steps (i) to (iii), (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is synthesized.

[0090] In one embodiment, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is prepared by reacting a compound of formula (III) with a compound of formula (IV) or a salt thereof prior to steps (i) to (iii): [ka]

[0091] Typically, a compound of formula (III) is reacted with a compound of formula (IV) in the presence of a base, for example an inorganic base such as potassium carbonate (K2CO3).

[0092] The reaction temperature varies depending on the solvent used. Preferably, the reaction is carried out using a nitrogen-containing solvent as the reaction solvent, and the reaction is heated to a temperature of 60°C to 70°C. Preferably, the nitrogen-containing solvent is N-methyl-2-pyrrolidone (NMP).

[0093] Under these conditions, complete conversion to (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is typically achieved in 8 to 12 hours.

[0094] Upon completion of the conversion, the reaction mixture is subjected to an aqueous workup to provide (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate. For example, the reaction mixture is diluted with water and an organic solvent, and the product is extracted from the reaction mixture in the organic solvent.

[0095] Compounds of formula (III) are prepared by reacting a compound of formula (I) with a compound of formula (II): [ka]

[0096] Typically, a compound of formula (I) is reacted with a compound of formula (II) in the presence of a base, for example, an inorganic base such as potassium carbonate (K2CO3).

[0097] The reaction temperature varies depending on the solvent used. Preferably, the reaction is carried out using a nitrogen-containing solvent as the reaction solvent, and the reaction is heated to a temperature of 70°C to 80°C during the reaction.

[0098] The nitrogen-containing solvent is typically an N-alkylpyrrolidinone, dimethylformamide, or dimethylacetamide.

[0099] Preferably, the nitrogen-containing solvent is N-methyl-2-pyrrolidone (NMP).

[0100] Under these conditions, complete conversion to the compound of formula (III) is usually achieved in 2 to 6 hours.

[0101] The reaction may also be carried out in the presence of a catalyst, preferably in the presence of a catalyst and an antioxidant compound.

[0102] The catalyst is preferably an iodide salt, such as potassium iodide, sodium iodide, lithium iodide or ammonium iodide. Most preferably, the catalyst is potassium iodide.

[0103] It is understood that the catalyst, particularly an iodide salt, advantageously increases the reaction rate in the direction of compound (III), however, it is also understood that the iodide salt may react with the reaction solvent, particularly if the reaction solvent is a nitrogen-containing solvent (e.g., NMP, etc.).

[0104] The present inventors have surprisingly discovered that the reaction of iodide salts with nitrogen-containing solvents can be suppressed or eliminated when the reaction is carried out in the presence of an iodide salt and an antioxidant compound.

[0105] This is particularly advantageous as the reaction proceeds in the presence of a catalyst, reducing the formation of by-products, which in turn increases both the reaction yield and the purity of the reaction product.

[0106] The antioxidant compound is selected from butylated hydroxyanisole, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, gallic acid, butylated hydroquinone and phenol.

[0107] Preferably, the antioxidant compound is butylated hydroxyanisole.

[0108] In one embodiment, prior to carrying out steps (i) to (iii), (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is prepared according to the following one-pot method: [ka]

[0109] For the avoidance of any doubt, a one-pot process is a process / reaction in which reactants are subjected to successive chemical reactions in a single reaction vessel (multi-step synthesis).

[0110] Upon completion of the conversion, the reaction mixture is subjected to an aqueous workup to afford (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate. For example, the reaction mixture is diluted with water and an organic solvent, and the product is extracted from the reaction mixture in the organic solvent.

[0111] Advantageously, after this one-pot procedure, once the above-defined process steps (i) to (iii) are completed, the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate can be isolated in high yield and purity.

[0112] Therefore, the present inventors have prepared and isolated solid (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate as described above, thereby obtaining a compound of formula (III) by reacting compounds of formula (I) and formula (II). and reacting compounds of formula (III) and formula (IV) to form (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, can be carried out in one pot.

[0113] In particular, by preparing and isolating the solid form according to the methods defined herein, a one-pot process can be used, due to the fact that the solid form can be obtained substantially in the absence of impurities and by-products.

[0114] In particular, isolation of the solid form from the one-pot process effectively removes intermediate by-products that are typically formed during the reaction of compounds of formula (I) and (II) to form compounds of formula (III).

[0115] Therefore, the method for producing the solid form is a one-pot process that is viable in terms of overall yield and purity of the product obtained.

[0116] Preferably, the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by the process described hereinabove is a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0117] The quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by this method is defined and characterized as above.

[0118] The one-pot method is carried out by using the synthetic procedure defined hereinabove.

[0119] In particular, a compound of formula (I) is reacted with a compound of formula (II) in the presence of a base, for example, an inorganic base such as potassium carbonate (K2CO3).

[0120] The reaction temperature varies depending on the solvent used. Preferably, the reaction is carried out using a nitrogen-containing solvent as the reaction solvent, and the reaction is heated to a temperature of 70°C to 80°C. Preferably, the nitrogen-containing solvent is N-methyl-2-pyrrolidone (NMP).

[0121] Under these conditions, complete conversion to the compound of formula (III) is usually achieved in 2 to 6 hours.

[0122] The reaction is also carried out in the presence of a catalyst, preferably an iodide salt, as described above, and preferably in the presence of a catalyst and an antioxidant compound.

[0123] Once the conversion to the compound of formula (III) is complete, the compound of formula (IV) and an inorganic base (e.g., potassium carbonate) and a solvent (e.g., NMP) are added to the same reaction vessel at a temperature of 70°C to 80°C.

[0124] Preferably, after adding these reagents, the reaction mixture is cooled from a temperature of 70°C to 80°C to a temperature of 60°C to 70°C, and the reaction mixture is stirred.

[0125] Under these conditions, complete conversion to (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is typically achieved in 8 to 12 hours.

[0126] A solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is then isolated by the methods described herein.

[0127] The present invention also provides a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by the process described herein.

[0128] In one embodiment, the present invention provides a semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by the process described herein.

[0129] The present invention also provides a semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, as defined and characterized herein, obtainable by the process described herein.

[0130] In particular, the present invention provides (i) dissolving (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in dichloromethane to form a solution; (ii) adding methyl tert-butyl ether to the solution; and (iii) recovering the resulting precipitate from said solution. The present invention provides a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by a process comprising:

[0131] The present invention also provides (i) dissolving (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in dichloromethane to form a solution; (ii) adding methyl tert-butyl ether to the solution; and (iii) recovering the resulting precipitate from said solution. The present invention provides a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate obtained by a process comprising:

[0132] As described herein, the process yields a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate that has beneficial physical properties that allow for the isolation of a key intermediate in the synthesis of linagliptin in high yield and purity, effectively free of intermediate by-products and impurities.

[0133] Accordingly, the present invention also provides use of a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate for the production of linagliptin or a salt thereof.

[0134] In one embodiment, the present invention provides use of the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate for the preparation of linagliptin or a salt thereof.

[0135] The present invention also provides the use of the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, as defined and characterized herein, for the preparation of linagliptin or a salt thereof.

[0136] Accordingly, the present invention also provides the use of a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, prepared by the method described herein, for the production of linagliptin or a salt thereof.

[0137] In one embodiment, the present invention provides use of the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, prepared by the method described herein, for the preparation of linagliptin or a salt thereof.

[0138] The present invention also provides the use of the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate as defined and characterized herein and prepared by the process described herein, for the preparation of linagliptin or a salt thereof.

[0139] To prepare linagliptin, the tert-butyloxycarbonyl protecting group is simply removed from (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0140] Those skilled in the art will be aware from their common knowledge of the various procedures by which this protecting group may be removed.

[0141] Preferably, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is reacted with an acid to produce linagliptin or its salt linagliptin.

[0142] Furthermore, a person skilled in the art would be aware from his or her general knowledge of a variety of acids and acidic conditions suitable for removing the tert-butyloxycarbonyl protecting group to prepare linagliptin.

[0143] Preferably, sulfuric acid, hydrochloric acid or trifluoroacetic acid is used to remove the tert-butyloxycarbonyl protecting group.

[0144] The present invention also includes the use of the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, as defined and characterized herein and prepared by the process described herein, for the manufacture of a linagliptin dosage form, comprising combining linagliptin with one or more pharmaceutically acceptable excipients to provide a linagliptin dosage form.

[0145] Linagliptin is usually administered orally, and therefore the dosage form is preferably an oral dosage form, most preferably a tablet. In such cases, the method further comprises a tableting step. The oral dosage form may be a coated or uncoated tablet and is manufactured using standard techniques known in the art.

[0146] The dose of linagliptin is usually 5 mg given orally once daily. When linagliptin is added to metformin, the metformin dose should be maintained and linagliptin should be co-administered.

[0147] Other preferred embodiments of the present invention include:

[0148] 1. A method for preparing linagliptin or a salt thereof, comprising: (a) reacting a compound of formula (I) with a compound of formula (II) to prepare a compound of formula (III), wherein the reaction is carried out in the presence of a catalyst and an antioxidant compound: [ka] and (b) converting the compound of formula (III) to linagliptin The method comprising:

[0149] 2. The method of embodiment 1, wherein the catalyst is an iodide salt.

[0150] 3. The method of embodiment 1 or 2, wherein the catalyst is selected from potassium iodide, sodium iodide, lithium iodide, or ammonium iodide.

[0151] 4. The method of any one of embodiments 1-3, wherein the antioxidant compound is selected from butylated hydroxyanisole, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, gallic acid, butylated hydroquinone, and phenol.

[0152] 5. The method of any one of embodiments 1 to 4, wherein step (a) is carried out in a nitrogen-containing solvent, preferably in a solvent of N-alkylpyrrolidinone, dimethylformamide, or dimethylacetamide.

[0153] 6. The method of any one of embodiments 1 to 5, wherein steps (a) and (b) are carried out in one pot.

[0154] 7. A method for producing linagliptin or a salt thereof, comprising: (a) reacting a compound of formula (I) with a compound of formula (II) to produce a compound of formula (III), wherein the reaction is carried out in the presence of a catalyst and an antioxidant compound: [ka] (b) reacting a compound of formula (III) with a compound of formula (IV) or a salt thereof to prepare a compound of formula (V): [ka] and (c) converting the compound of formula (V) to linagliptin The method comprising:

[0155] 8. The method of embodiment 7, wherein the catalyst is an iodide salt.

[0156] 9. The method of embodiment 7 or 8, wherein the catalyst is selected from potassium iodide, sodium iodide, lithium iodide, or ammonium iodide.

[0157] 10. The method of any one of embodiments 7-9, wherein the antioxidant compound is selected from butylated hydroxyanisole, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, gallic acid, butylated hydroquinone, and phenol.

[0158] 11. The method of any one of embodiments 7 to 10, wherein step (a) is carried out in a nitrogen-containing solvent, preferably in a solvent of N-alkylpyrrolidinone, dimethylformamide, or dimethylacetamide.

[0159] 12. The method of any one of embodiments 7 to 11, wherein steps (a) and (b) are carried out in one pot, and optionally steps (a), (b) and (c) are carried out in one pot.

[0160] 13. Linagliptin or a salt thereof obtainable by the method according to any one of embodiments 1 to 6, or linagliptin or a salt thereof obtainable by the method according to any one of embodiments 7 to 12.

[0161] 14. Use of linagliptin or a salt thereof prepared by the method according to any one of embodiments 1 to 6 or the method according to any one of embodiments 7 to 12 for preparing a linagliptin dosage form.

[0162] 15. Use of linagliptin or a salt thereof according to embodiment 13 for the manufacture of a linagliptin dosage form.

[0163] In these embodiments, the present invention provides a method for preparing linagliptin or a salt thereof, comprising: (a) reacting a compound of formula (I) with a compound of formula (II) to prepare a compound of formula (III), wherein the reaction is carried out in the presence of a catalyst and an antioxidant compound: [ka] and (b) converting the compound of formula (III) to linagliptin The present invention relates to a method comprising the steps of:

[0164] The present invention also provides a method for preparing linagliptin or a salt thereof, comprising: (a) reacting a compound of formula (I) with a compound of formula (II) to prepare a compound of formula (III), wherein the reaction is carried out in the presence of a catalyst and an antioxidant compound: [ka] (b) reacting a compound of formula (III) with a compound of formula (IV) or a salt thereof to prepare a compound of formula (V): [ka] and (c) converting the compound of formula (V) to linagliptin The present invention relates to a method comprising the steps of:

[0165] For these processes, the catalyst is preferably an iodide salt, such as potassium iodide, sodium iodide, lithium iodide or ammonium iodide. Most preferably, the catalyst is potassium iodide.

[0166] Similarly, the antioxidant compound is selected from butylated hydroxyanisole, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, gallic acid, butylated hydroquinone and phenol.

[0167] Preferably, the antioxidant compound is butylated hydroxyanisole.

[0168] Typically, the compound of formula (I) is reacted with the compound of formula (II) in the presence of a base, for example, an inorganic base such as potassium carbonate (K2CO3).

[0169] The reaction temperature varies depending on the solvent used. Preferably, the reaction is carried out using a nitrogen-containing solvent as the reaction solvent, and the reaction is heated to a temperature of 70°C to 80°C during the reaction.

[0170] The nitrogen-containing solvent is typically an N-alkylpyrrolidinone, dimethylformamide, or dimethylacetamide.

[0171] Preferably, the nitrogen-containing solvent is N-methyl-2-pyrrolidone (NMP).

[0172] Under these conditions, complete conversion to the compound of formula (III) is usually achieved in 2 to 6 hours.

[0173] It will be appreciated that the catalyst (especially the iodide salt) advantageously increases the reaction rate in the direction of compound (III).

[0174] However, it is also understood that iodide salts may react with the reaction solvent, especially if the reaction solvent is a nitrogen-containing solvent (such as NMP).

[0175] The present inventors have surprisingly discovered that the reaction between an iodide salt and a nitrogen-containing solvent can be suppressed or eliminated if the reaction is carried out in the presence of an iodide salt catalyst and an antioxidant compound.

[0176] This is particularly advantageous as it allows the reaction to proceed in the presence of a catalyst and reduces the formation of by-products.

[0177] Thus, the present inventors have unexpectedly discovered that the use of a catalyst and an antioxidant compound increases the yield and purity of compound (III) compared to a process in which the antioxidant compound is not present.

[0178] As a result, since compound (III) (8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione) is a key intermediate leading to linagliptin, this synthetic step can be advantageously used as part of a simplified synthesis to produce linagliptin in increased purity and / or yield.

[0179] In particular, the process for preparing the compound of formula (III) in the presence of a catalyst and an antioxidant makes the one-pot process viable in terms of overall yield and purity of the product obtained.

[0180] Therefore, steps (a) and (b) of the methods described in embodiments 1 to 5 are carried out in one pot.

[0181] Similarly, steps (a) and (b), or steps (a), (b) and (c) of the methods described in embodiments 7 to 11 are carried out in one pot.

[0182] To prepare linagliptin, the tert-butyloxycarbonyl protecting group is simply removed from (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound V).

[0183] A person skilled in the art will be aware from his common general knowledge of the various procedures by which this protecting group can be removed.

[0184] Preferably, (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is reacted with an acid to produce linagliptin or a salt thereof.

[0185] Furthermore, a person skilled in the art would be aware from his or her general knowledge of a variety of acids and acidic conditions suitable for removing the tert-butyloxycarbonyl protecting group to prepare linagliptin.

[0186] Preferably, sulfuric acid, hydrochloric acid or trifluoroacetic acid is used to remove the tert-butyloxycarbonyl protecting group.

[0187] Linagliptin or a salt thereof can also be obtained by the method according to any one of embodiments 1-6, or by the method according to any one of embodiments 7-12.

[0188] Additionally, linagliptin or a salt thereof prepared by the method according to any one of embodiments 1 to 6 or the method according to any one of embodiments 7 to 12 is used to prepare a linagliptin dosage form.

[0189] Also, the linagliptin or salt thereof according to embodiment 13 is used to prepare a linagliptin dosage form.

[0190] The present invention will be described below based on examples, but the present invention is not limited to these examples. [Example]

[0191] General method The semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate was characterized as follows.

[0192] The sample was ground and subjected to XRPD. The spectrum is shown in Figure 1. XRPD spectra were obtained using a Rigaku MiniFlex 600 X-ray diffractometer (Bragg-Brentano geometry) with Cu-Kα radiation (1.5406 Å) within an angular range of 2-40° 2θ at 0.01° increments and a scan rate of 6.0° / min. The limiting slit was adjusted to 10 mm, and a Kβ filter was used simultaneously.

[0193] The crystallinity is calculated by XRD (X-ray diffraction) deconvolution method. The deconvolution of the X-ray diffraction pattern is performed by ORIGIN PRO 8.5 software, which considers the shape of the resolved peaks as a Gaussian function. The crystallinity is calculated by one of the following formulas: CI(%) = 100 × Sc / St; or CI(%)=100-(Sa / St×100) In the formula, Sc represents the area of ​​the crystalline domain, Sa represents the area of ​​the amorphous domain, and St represents the area of ​​all domains.

[0194] Thus, a crystallinity of 25% to 75% means that the sample contains 25% to 75% crystalline material.

[0195] Differential scanning calorimetry (DSC) and infrared spectroscopy were also used. The DSC trace and IR spectrum are shown in Figures 2 and 3, respectively.

[0196] DSC was performed using a Mettler-Toledo Star DSC1 instrument at a heating rate of 2.5°C / min. The DSC onset was 144.84°C, the peak was 154.88°C, and the end was 157.10°C.

[0197] IR spectra were obtained according to the European Pharmacopoeia (2.2.24.) and the United States Pharmacopoeia <197K> using the KBr disk method. The instrument was a Perkin Elmer SPECTRUM TWO.

[0198] The list of IR peaks is as follows (cm -1 ):3333.95;2942.79;1701.86;1664.74;1621.76;1569.08;1515.67;1439.86;1401.37;1365.81;1311.49;1288.48;1245.09;1167.28;1129.38;1054.48;953.96;761.35;595.61.

[0199] The purity of the obtained (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate was assessed by UPLC (ultra performance liquid chromatography) with a UV detector according to the following protocol.

[0200] column: -Acquity UPLC BEH C18 2.1 × 100 mm; particle size, 1.7 μm (Waters, catalog number 186002352);

[0201] Mobile phase: Mobile phase A: 0.1% orthophosphoric acid / water (1.0 mL of orthophosphoric acid (85%) is added to 1000 mL of purified water, mixed and degassed using a sonication bath); - Mobile phase B: acetonitrile;

[0202] Flow rate: 0.3mL / min. Detection: spectrophotometer, 228 nm. Injection: 1.0 μL of test solution.

[0203] Standard solution I: Approximately 20.0 mg of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound V) standard is accurately weighed into a 100 mL volumetric flask, dissolved in diluent using a sonication bath, and made up to volume with diluent.

[0204] Standard solution II: Approximately 20.0 mg of 8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione (Compound III) standard is accurately weighed into a 100 mL volumetric flask, dissolved in diluent using a sonication bath, and made up to volume with diluent.

[0205] Standard solution III: Transfer 1.0 mL of Standard Solution I and 1.0 mL of Standard Solution II to a 50 mL volumetric flask and make up to volume with diluent.

[0206] Standard solutions: Transfer 1.0 mL of standard solution III to a 20 mL volumetric flask and make up to volume with diluent (Compound III, 0.10%; Compound V, 0.10%).

[0207] Test solution I: Approximately 20.0 mg of test substance is accurately weighed into a 100 mL volumetric flask, dissolved in diluent, and made up to volume with diluent (0.2 mg / mL).

[0208] Test Solution II: Transfer 1.0 mL of Test Solution I to a 50 mL volumetric flask and make up to volume with diluent.

[0209] Column conditioning: Conditioning of the column begins with a flow rate of 0.20 mL / min of mobile phase A:mobile phase B (90:10, v / v) for 10 minutes at a temperature of 40°C, and the flow rate is gradually increased to 0.30 mL / min. The flow rate is maintained until the back pressure stabilizes. The baseline is monitored until it stabilizes.

[0210] The analytical method is based on a mobile phase gradient, therefore two chromatographic runs without injection (condition column) and several injections of diluent were performed.

[0211] procedure: After equilibrating the chromatographic system, the analysis of the diluent, standard solution, standard solution III, test solution II and test solution I was carried out, the chromatograms of each were recorded and the purity of the substances contained in the test solutions was calculated accordingly.

[0212] The retention time for R)-tert-Butyl(1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate according to this protocol is approximately 7.1 minutes.

[0213] Example 1: Preparation of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound V) [ka]

[0214] 2-(Chloromethyl)-4-methyl-quinazoline (Compound I) (66.13 g, 0.343 mol) and 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (Compound II) (100.00 g, 0.337 mol), potassium carbonate (53.50 g, 0.387 mol), potassium iodide (2.79 g, 0.017 mol), and N-methyl-2-pyrrolidone (450 mL) were charged to a reactor. Immediately after stirring, the reaction mixture was heated to 75-80 °C and stirred for 4 h. The reaction then proceeded to completion, yielding 8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione (Compound III).

[0215] Compound (IV) (77.52 g, 0.387 mol), potassium carbonate (53.50 g, 0.387 mol), and N-methyl-2-pyrrolidone (50 mL) were then charged directly to the reactor containing compound III. After the addition was complete, the reaction mixture was cooled to 60-65°C and stirred for 10 hours.

[0216] After the reaction was complete, toluene (750 mL) was added to the mixture, and the resulting suspension was stirred for 30 minutes. Next, water (500 mL) was added dropwise to the suspension over 1 hour, and the mixture was then stirred at 80-85°C for an additional 1 hour. Then, stirring was stopped, and the layers were separated. The toluene layer was collected, and the aqueous layer was extracted with toluene (500 mL). The combined toluene layers were transferred to a reactor and washed with 10% brine solution (500 mL), followed by water (500 mL). The toluene layer was then collected and evaporated to dryness. Dichloromethane (DCM) (100 mL) was then added to the dry residue, which was then removed by evaporation.

[0217] The crude (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate residue was then dissolved in dichloromethane (300 mL) at 30° C. To this solution was charged activated carbon (20.0 g) and magnesium sulfate (30.0 g). The resulting suspension was stirred for 2 hours, after which the solids were removed by filtration. The filtrate was then heated to 35° C., and methyl tert-butyl ether (MTBE) (1500 mL) was added dropwise to the filtrate. Upon complete addition of methyl tert-butyl ether, the solution was cooled to 5° C. at a rate of −10° C. / hour and stirred at this temperature for an additional 2 hours.

[0218] The resulting precipitate was filtered, washed with DCM:MTBE (1:4 solution) (200 mL), and then dried in a vacuum oven at 50° C. / 20 mbar to give the quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0219] Obtained 144.66 g of a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (75.0% yield from compound II; 97.5-98% purity, determined by UPLC). The compound was obtained as a pure white to off-white solid.

[0220] Example 2 Preparation of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound V) [ka]

[0221] 2-(Chloromethyl)-4-methyl-quinazoline (Compound I) (66.13 g, 0.343 mol) and 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (Compound II) (100.00 g, 0.337 mol), potassium carbonate (53.50 g, 0.387 mol), potassium iodide (2.79 g, 0.017 mol), butylated hydroxyanisole (3.03 g, 0.017 mol), and N-methyl-2-pyrrolidone (450 mL) were charged into a reactor. Immediately after stirring, the reaction mixture was heated to 75-80 °C and stirred for 4 h. After this time the reaction should proceed to completion to give 8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione (compound III).

[0222] Compound (IV) (77.52 g, 0.387 mol), potassium carbonate (53.50 g, 0.387 mol), and N-methyl-2-pyrrolidone (50 mL) were then charged directly to the reactor containing compound III. After the addition was complete, the reaction mixture was cooled to 60-65°C and stirred for 10 hours.

[0223] After the reaction was complete, toluene (750 mL) was added to the mixture, and the resulting suspension was stirred for 30 minutes. Next, water (500 mL) was added dropwise to the suspension over 1 hour, and the mixture was then stirred at 80-85°C for an additional 1 hour. Then, the stirring was stopped, and the layers were separated. The toluene layer was collected, and the aqueous layer was extracted with toluene (500 mL). The combined toluene layers were transferred to a reactor and washed with 10% brine solution (500 mL), followed by water (500 mL). The toluene layer was then collected and evaporated to dryness. Dichloromethane (DCM) (100 mL) was then added to the dry residue and removed by evaporation.

[0224] The crude (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate residue was then dissolved in dichloromethane (300 mL) at 30° C. To this solution was charged activated carbon (20.0 g) and magnesium sulfate (30.0 g). The resulting suspension was stirred for 2 hours, after which the solids were removed by filtration. The filtrate was then heated to 35° C., and methyl tert-butyl ether (MTBE) (1500 mL) was added dropwise to the filtrate. Upon complete addition of methyl tert-butyl ether, the solution was cooled to 5° C. at a rate of −10° C. / hour and stirred at this temperature for an additional 2 hours.

[0225] The resulting precipitate was filtered, washed with DCM:MTBE (1:4 solution) (200 mL), and then dried in a vacuum oven at 50° C. / 20 mbar to give a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0226] 165.42 g of a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate was obtained (85.8% yield from compound II; 98.5-99% purity, determined by UPLC).

[0227] Example 2a: Preparation of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound V) [ka]

[0228] 2-(Chloromethyl)-4-methyl-quinazoline (Compound I) (66.13 g, 0.343 mol) and 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (Compound II) (100.00 g, 0.337 mol), potassium carbonate (53.50 g, 0.387 mol), potassium iodide (2.79 g, 0.017 mol), butylated hydroxyanisole (3.03 g, 0.017 mol), and N-methyl-2-pyrrolidone (450 mL) were charged into a reactor. Immediately after stirring, the reaction mixture was heated to 75-80 °C and stirred for 4 h. After this time the reaction should proceed to completion to give 8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione (compound III).

[0229] Compound (IV) (77.52 g, 0.387 mol), potassium carbonate (53.50 g, 0.387 mol), and N-methyl-2-pyrrolidone (50 mL) were then charged directly to the reactor containing compound III. After the addition was complete, the reaction mixture was cooled to 60-65°C and stirred for 10 hours.

[0230] After the reaction was complete, toluene (750 mL) was added to the mixture, and the resulting suspension was stirred for 30 minutes. Next, water (500 mL) was added dropwise to the suspension over 1 hour, and the mixture was stirred at 80-85°C for an additional 1 hour. Then, stirring was stopped, and the layers were separated. The toluene layer was collected, and the aqueous layer was extracted with toluene (500 mL). The combined toluene layers were transferred to a reactor and washed with 10% brine solution (500 mL), followed by water (500 mL). The toluene layer was then collected and evaporated to dryness. Dichloromethane (DCM) (200 mL) was then added to the dry residue and removed by evaporation.

[0231] The crude (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate residue was then dissolved in dichloromethane (300 mL) at 30 °C. Activated carbon (30.0 g) and magnesium sulfate (30.0 g) were added to the solution. The resulting suspension was stirred for 2 h, and the solids were removed by filtration. The filtrate was then heated to 35-40 °C, and methyl tert-butyl ether (MTBE) (22,500 mL) was added dropwise to the filtrate while maintaining the temperature at 35-40 °C. Upon completion of the MTBE addition, the solution was cooled to 0-10 °C at a rate of -10 °C / h and stirred at this temperature for an additional 2 h.

[0232] The resulting crystalline precipitate was filtered and washed with DCM:MTBE (1:4.5 solution) (200 mL, 2 times). The precipitate was then recharged to the reaction vessel, and DCM:MTBE (1:4.5 solution) (1250 mL) was added. The resulting mixture was then stirred for 2 hours. The mixture was then filtered, and the collected solid product was washed with DCM:MTBE (1:4.5 solution) (200 mL, 2 times). The product was then dried in a vacuum oven at 50°C / 20 mbar to obtain a quasi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

[0233] 126.5 g of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in a quasi-amorphous form was obtained (83.0% yield from compound II; >99.1% purity, as determined by UPLC). The compound was obtained as a pure white to off-white solid.

[0234] Example 3 Preparation of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (Compound V) [ka]

[0235] 2-(Chloromethyl)-4-methyl-quinazoline (Compound I) (66.13 g, 0.343 mol) and 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (Compound II) (100.00 g, 0.337 mol), potassium carbonate (53.50 g, 0.387 mol), potassium iodide (2.79 g, 0.017 mol), butylated hydroxyanisole (3.03 g, 0.017 mol), and N-methyl-2-pyrrolidone (450 mL) were charged into a reactor. Immediately after stirring, the reaction mixture was heated to 75-80 °C and stirred for 4 h. After this time the reaction should proceed to completion to give 8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione (compound III).

[0236] Compound (IV) (77.52 g, 0.387 mol), potassium carbonate (53.50 g, 0.387 mol), and N-methyl-2-pyrrolidone (50 mL) were then charged directly to the reactor containing compound III. After the addition was complete, the reaction mixture was cooled to 60-65°C and stirred for 10 hours.

[0237] After the reaction was complete, toluene (750 mL) was added to the mixture, and the resulting suspension was stirred for 30 minutes. Next, water (500 mL) was added dropwise to the suspension over 1 hour, and the mixture was then stirred at 80-85°C for an additional 1 hour. Then, the stirring was stopped, and the layers were separated. The toluene layer was collected, and the aqueous layer was extracted with toluene (500 mL). The combined toluene layers were transferred to a reactor and washed with 10% brine solution (500 mL), followed by water (500 mL). The toluene layer was then collected and evaporated to dryness. Dichloromethane (DCM) (100 mL) was then added to the dry residue and removed by evaporation.

[0238] The crude (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate residue was then dissolved in dichloromethane (300 mL) at 30° C. Activated carbon (20.0 g) and magnesium sulfate (30.0 g) were charged to this solution. The resulting suspension was stirred for 2 hours, after which the solid matter was removed by filtration. The filtrate was then heated to 35° C. and all volatiles were removed by evaporation under reduced pressure. Finally, the resulting product was dried in a vacuum oven at 50° C. / 20 mbar.

[0239] 165.42 g of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate was obtained (85.8% yield from compound II; 96% purity, determined by UPLC).

[0240] Example 4: Preparation of 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione (linagliptin) [ka]

[0241] (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate (100.00 g, 0.175 mol), MeOH (1000 mL), water (500 mL), and 98% sulfuric acid (46.80 mL, 85.64 g, 0.87 mol) were charged to a reactor. After thorough mixing at room temperature, the reaction mixture was heated to 60°C and stirred until dissolved, then stirred for 4 hours. The MeOH / water phase was then cooled to 30°C, the pH was adjusted to 11.5-12.5 with 30% NaOH solution, and the mixture was stirred for an additional 2 hours. The resulting suspension was then filtered, and the filtrate was collected and combined with dichloromethane (500 mL) and 10% brine solution (500 mL), then transferred to a reactor. The reaction mixture remained at 30°C during this time. After stirring for 0.5 hours, the phases were separated, the dichloromethane layer was collected, and the aqueous layer was extracted with dichloromethane (250 mL). The aqueous layer was then discarded, while the collected organic layers were combined and washed with 10% brine solution (500 mL), followed by water (500 mL). Water (1000 mL) and acetic acid (40 mL) were then added to the dichloromethane layer, stirred for 0.5 hours, and then separated. The aqueous layer was left in the reactor and washed twice with dichloromethane (250 mL). After washing, dichloromethane (500 mL) was added, the pH was adjusted again to 11.5-12.5, and the mixture was stirred for an additional 0.5 h. The phases were then separated and the dichloromethane layer was collected. The aqueous layer was re-extracted with dichloromethane (250 mL), and this dichloromethane was again separated and combined with the previous dichloromethane layer. The combined dichloromethane solution was washed twice with water (500 mL). All volatiles were then evaporated by distillation (40 °C), followed by vacuum distillation (up to 60 °C / 20 mbar).

[0242] EtOH (300 mL) and MTBE (25 mL) were added to the resulting dry residue, and the mixture was heated to 50° C. and stirred until complete dissolution. MTBE (1200 mL) was then added dropwise to the solution, and the resulting crystalline suspension was stirred at 50° C. for 1 hour and then cooled to −10° C. at a rate of −10° C. / min. The mixture was then stirred at this temperature for another 2 hours. The resulting precipitate was filtered, washed with EtOH:MTBE (1:4 solution) (100 mL), and then dried in a vacuum oven at 35° C. / 20 mbar. 72.4 g (89.9%) of crude linagliptin was obtained.

[0243] Example 5: Recrystallization of 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione (linagliptin) Linagliptin (50.00 g, 0.106 mol) was charged into a reactor, followed by EtOH (150 mL) and MTBE (12.5 mL). The mixture was heated to 50° C. and stirred until dissolved. MTBE (600 mL) was then added dropwise to the solution, and the resulting crystalline suspension was stirred at 50° C. for 1 hour and then cooled to −10° C. at a rate of −10° C. / min. The mixture was then stirred at this temperature for another 2 hours. The resulting precipitate was filtered, washed with EtOH:MTBE (1:4 solution) (50 mL), and then dried in a vacuum oven at 35° C. / 20 mbar. 45.5 g (91.0%) of linagliptin was obtained.

Claims

1. A semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate.

2. 2. The semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate according to claim 1, characterized by XRPD peaks at 2θ (°) ±0.2°: 3.0, 10.3, 15.3, 18.8, 21.4 and 26.

5.

3. 3. The semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate according to claim 1 or 2, characterized by broad XRPD peaks, the width of each peak being at the base of each peak within the following ranges, 2θ (°) ±0.2°: 2.3 to 4.0, 9.7 to 10.7, 14.8 to 15.8, 20.5 to 22.5, and 25.8 to 27.

5.

4. The quasi-amorphous form of (R)-(1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate of any one of claims 1 to 3, characterized by a differential scanning calorimetry (DSC) thermogram with a melting onset of 144-146°C, a melting end of 156-158°C, and a melting point peak of 154-156°C.

5. 1. A process for the preparation of a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, comprising: (i) dissolving (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate in dichloromethane to form a solution; (ii) adding methyl tert-butyl ether to the solution; and (iii) recovering the resulting precipitate from said solution. The method comprising:

6. Prior to the steps (i) to (iii), (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is reacted with a compound of formula (III) or a salt thereof: 【Chemical 1】 The method of claim 5, wherein the compound is produced by

7. a compound of formula (III) by reacting a compound of formula (I) with a compound of formula (II) 【Chemistry 2】 The method of claim 6, wherein the compound is produced by

8. (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate can be prepared by the following method, which is a one-pot method: 【Chemistry 3】 The method according to any one of claims 5 to 7, wherein the composition is produced according to the following formula:

9. 9. The process according to claim 7 or 8, wherein the compound of formula (III) is prepared by reacting a compound of formula (I) with a compound of formula (II) in the presence of a catalyst, preferably in the presence of a catalyst and an antioxidant compound.

10. 10. The method of claim 9, wherein the antioxidant compound is selected from butylated hydroxyanisole, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, gallic acid, butylated hydroquinone, and phenol.

11. 11. The method of any one of claims 5 to 10, wherein the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate is the quasi-amorphous form of any one of claims 1 to 4.

12. A solid form of (R)-tert-butyl(1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, obtainable by the method according to any one of claims 5 to 10.

13. Use of the semi-amorphous form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate according to any one of claims 1 to 4, or use of the solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate according to claim 12, for the manufacture of linagliptin or a salt thereof.

14. Use of a solid form of (R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate, produced by the method according to any one of claims 5 to 11, for producing linagliptin or a salt thereof.

15. 15. The use according to claim 13 or 14, comprising combining linagliptin with one or more pharmaceutically acceptable excipients to obtain a linagliptin dosage form.

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