Preparation method of linagliptin

Abstract

The invention relates to the technical field of pharmacy, and discloses a linagliptin preparation method, which comprises: 1, reacting a compound a and a compound b under an alkaline condition, according to the preparation method of the linagliptin, the high-purity linagliptin is prepared through reaction steps of aromatic nucleophilic substitution reaction, substitution, deprotection and the like and screening reaction conditions of proper material proportion, reaction time, reaction temperature, post-treatment mode and the like, and the process reaction of the method is relatively mild in conditions in the preparation process of an intermediate g; the reaction time is greatly shortened, the mixed solvent is used for crystallization, effective solidification of the product can be realized, the product can be efficiently separated, the product purity is improved, in the process of removing tert-butyl carbonyl protection, efficient dissociation of impurities of a dimer can be realized under the alkaline condition, so that the high-purity linagliptin raw material is obtained, the new raw material is easy to obtain, the production cost is low, and the method is suitable for industrial production. The industrial production requirements of linagliptin can be met to the greatest extent.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceuticals, and particularly to a preparation method of linagliptin. Background Art

[0002] The chemical name of linagliptin is (8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione), and its chemical structural formula is as shown in Formula H. It is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, which can prolong the half-life of active glucagon-like peptide-1 (GLP-1) in the body by inhibiting DPP-4, thereby achieving the effect of treating type 2 diabetes, showing high selectivity, good safety and tolerance.

[0003]

[0004] In the prior art, there are already multiple synthetic routes for linagliptin raw materials. Among them, the synthetic route disclosed in Patent WO2004018468A has simple and easily available raw materials, relatively mild reaction conditions, and relatively reasonable route steps. However, there are major problems in the preparation process of intermediate g. The reaction time is long, the reaction conditions are relatively severe, and it is difficult to solidify intermediate g during actual operation, and a paste is often obtained, which is difficult to separate and purify. In the process of removing the tert-butyl carbonyl protection in the last step, a dimer impurity as shown in Formula I will be generated, and this impurity is difficult to remove, affecting the product yield and purity. In view of the problems existing in the current process, there is an urgent need to provide a preparation method that is easy to operate, easy to separate and purify, and can effectively inhibit dimer impurities.

[0005] Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides a preparation method of linagliptin, which has the advantages that the conditions in the preparation process of intermediate g are relatively mild, the reaction time is greatly shortened, the use of a mixed solvent for crystallization can achieve effective solidification of the product, the product can be efficiently separated, and the product purity is improved. In the process of removing the tert-butyl carbonyl protection, the alkaline conditions can achieve efficient dissociation of the dimer impurity, thereby obtaining a high-purity linagliptin raw material. The new raw materials are easily available, the production cost is low, and it can meet the industrial production requirements of linagliptin to the greatest extent, solving the problems raised in the background art.

[0007] The present invention provides the following technical solution: A preparation method of linagliptin, comprising the following steps:

[0008] Step 1: Compound a reacts with compound b under alkaline conditions, at a certain temperature, in an organic solvent to form compound c, and the reaction is

[0009]

[0010] Step 2: Compound c reacts with compound d under alkaline conditions, at a certain temperature, in an organic solvent to form compound e, and the reaction is

[0011]

[0012] Step 3: Compound e reacts with compound f under alkaline conditions, at a certain temperature, in an organic solvent to form compound g, and the reaction is

[0013]

[0014] Step 4: Compound g undergoes deprotection by reaction under acidic conditions, at a certain temperature, in an organic solvent, and then depolymerizes under alkaline conditions to obtain the final linagliptin product, and the reaction is

[0015]

[0016] Step 5: The crude linagliptin obtained in Step 4 is cooled and crystallized in an organic solvent at a certain temperature.

[0017] Preferably, the molar ratio of the feed of compound a to compound b in Step 1 is n(b):n(a) = 1.0 - 1.5.

[0018] Preferably, the molar ratio of the feed of compound c to compound d in Step 2 is n(d):n(c) = 1.0 - 1.5.

[0019] Preferably, the molar ratio of the feed of compound e to compound f in Step 3 is n(f):n(e) = 1.0 - 2.0.

[0020] Preferably, the alkali referred to in the alkaline conditions in Step 4 includes one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, ammonia water, etc., or an aqueous solution of the above alkali, and the concentration of the aqueous solution of the alkali is 2 mol / L to 6 mol / L.

[0021] Preferably, the alkali referred to in the alkaline conditions in Step 1, Step 2 and Step 3 is an organic base or an inorganic base substance, including one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, diisopropylethylamine, triethylamine, etc.

[0022] Preferably, the organic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, methanol, ethanol, acetonitrile, toluene, n-heptane or a mixture thereof, or a mixture of the above solvents and water.

[0023] Preferably, the certain temperature in Step 1, Step 2 and Step 3 is 40°C to 140°C; the certain temperature in Step 4 and Step 5 is -10°C to 100°C.

[0024] Preferably, the organic solvent in Step 5 is methanol, ethanol, isopropanol, tert-butanol, acetonitrile, n-heptane, ethyl acetate or a mixture thereof, or a mixture of the above solvents and water. For any of the preparation methods described above, the volume ratio of the anti-solvent to the solvent is 10:1 to 1:1; preferably 5:1 to 1:1.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] In the preparation method of linagliptin, 8-bromo-3-methyl-3,7-dihydro-purine-2,6-dione, that is, compound a, is used as the starting material. Through reaction steps such as aromatic nucleophilic substitution reaction, substitution, and deprotection, appropriate material ratios, reaction times, reaction temperatures, and post-treatment methods and other reaction conditions are screened to prepare high-purity linagliptin. The process reaction of this method is relatively mild in the preparation process of intermediate g, the reaction time is greatly shortened, and the use of a mixed solvent for crystallization can effectively solidify the product, and the product can be efficiently separated, improving the product purity. In the process of removing the tert-butyl carbonyl protection, the alkaline conditions can efficiently dissociate the impurities of the dimer, thereby obtaining high-purity linagliptin raw materials. The new raw materials are easily available, the production cost is low, and it can meet the industrial production requirements of linagliptin to the greatest extent. Description of the Drawings

[0027] Figure 1 It is the HPLC diagram of linagliptin of the present invention;

[0028] Figure 2 It is linagliptin of the present invention 1 1H-NMR diagram;

[0029] Figure 3 It is the summary diagram of HPLC data of the present invention. Detailed Embodiments

[0030] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0031] Please refer to Figures 1-3 , a preparation method of linagliptin, comprising the following steps:

[0032] Step 1: Compound a and compound b react in an organic solvent under alkaline conditions at a certain temperature to form compound c, and the reaction is

[0033]

[0034] Step 2: Compound c and compound d react in an organic solvent under alkaline conditions at a certain temperature to form compound e, and the reaction is

[0035]

[0036] Step 3: Compound e and compound f react in an organic solvent under alkaline conditions at a certain temperature to form compound g, and the reaction is

[0037]

[0038] Step 4: Compound g reacts under acidic conditions in an organic solvent at a certain temperature to deprotect, and then depolymerizes under alkaline conditions to obtain the final linagliptin product, and the reaction is

[0039]

[0040] Step 5: The crude linagliptin obtained in Step 4 is cooled and crystallized in an organic solvent at a certain temperature.

[0041] Among them, the molar ratio of compound a to compound b in Step 1 is n(b):n(a) = 1.0 - 1.5.

[0042] Among them, the molar ratio of compound c to compound d in Step 2 is n(d):n(c) = 1.0 - 1.5.

[0043] Among them, the molar ratio of compound e to compound f in Step 3 is n(f):n(e) = 1.0 - 2.0.

[0044] Among them, the acidic conditions in Step 4 are that the acid includes hydrochloric acid or trifluoroacetic acid, and the concentration of the hydrochloric acid solution is 2 mol / L to 12 mol / L.

[0045] Among them, the alkaline condition in Step 4 refers to that the base includes one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, ammonia water, etc., or an aqueous solution of the above bases, and the concentration of the aqueous solution of the base is 2 mol / L to 6 mol / L.

[0046] Among them, the alkaline conditions in Step 1, Step 2 and Step 3 refer to that the base is an organic base or an inorganic base substance, including one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, diisopropylethylamine, triethylamine, etc.

[0047] Among them, the organic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, methanol, ethanol, acetonitrile, toluene, n-heptane or a mixture thereof, or a mixture of the above solvents and water.

[0048] Among them, the certain temperature in Step 1, Step 2 and Step 3 is 40°C to 140°C.

[0049] Among them, the certain temperature in Step 4 and Step 5 is -10°C to 100°C.

[0050] Among them, the organic solvent in Step 5 is methanol, ethanol, isopropanol, tert-butanol, acetonitrile, n-heptane, ethyl acetate or a mixture thereof, or a mixture of the above solvents and water. For any of the preparation methods, the volume ratio of the antisolvent to the solvent is 10:1 to 1:1; preferably 5:1 to 1:1.

[0051] Example 1

[0052] A preparation method of linagliptin, Step 1:

[0053]

[0054] Add 100.0 g of compound a, 98.4 g of compound b, 67.9 g of potassium carbonate, and 400 ml of N-methylpyrrolidone into the reaction flask in sequence, control the temperature at 90°C and stir for reaction, monitor by TLC, until compound a basically reacts completely, cool to room temperature, control the temperature at 20 - 30°C and add 800 ml of water, stir for crystallization, filter, wash the filter cake with water, collect the filter cake, and dry it in a blast dryer at 60°C for 16 h to obtain 139.5 g of compound c, with a yield of 93.4%.

[0055] Step 2:

[0056]

[0057] Add 127.5 g of compound c, 1300 ml of N-methylpyrrolidone, and 543 g of diisopropylethylamine into the reaction flask in sequence. Raise the internal temperature to 60 °C, control the temperature at 60 - 70 °C, and dropwise add a solution of 485.1 g of compound d in NMP (130 ml). After addition, react at 70 °C for 1 h. Monitor by TLC until compound c has basically reacted completely. Cool the system to room temperature, control the temperature at 20 - 30 °C, add 2860 ml of water. After addition, stir at 20 - 30 °C for 1 - 2 h, filter by suction. Wash the filter cake successively with 380 ml of solvent (NMP / H2O: 1 / 2) and 640 ml of H2O. Collect the filter cake and dry it in a blast dryer at 60 - 70 °C for 16 h to obtain 131.6 g of compound e, with a yield of 90.3%.

[0058] Step 3:

[0059]

[0060] Add 125.0 g of compound e, 606.8 g of compound f, 580.0 g of K2CO3, 9.7 g of tetrabutylammonium bromide, and 2500 ml of N-methylpyrrolidone into the reaction flask in sequence. Raise the internal temperature to 60 °C and react for 4 h. Monitor by TLC until compound e has basically reacted completely. Cool the system to room temperature, control the temperature at 20 - 30 °C, add 2500 ml of water. After addition, cool to 5 - 15 °C and stir for 1 h, then filter. Wash the filter cake successively with NMP / H2O = 1 / 1 and water to obtain the crude product;

[0061] Purification:

[0062] Add 2500 ml of NMP to the crude product, raise the internal temperature to 80 °C and stir until dissolved clearly, then cool to room temperature. Control the temperature at 20 - 30 °C, add 2500 ml of water. After addition, cool to 5 - 15 °C and stir for 1 h, then filter. Wash the filter cake successively with NMP / H2O = 1 / 1.2 and water. Collect the filter cake and dry it in a blast dryer at 70 °C to obtain 142.9 g of compound g, with a yield of 83.2%.

[0063] Step 4:

[0064]

[0065] Add 114.5 g of compound g, 860 ml of dichloromethane, and 342.0 g of trifluoroacetic acid into the reaction flask in sequence. React at room temperature. Monitor by TLC until compound g has basically reacted completely. Dropwise add 1000 ml of 2M aqueous sodium hydroxide solution and stir for 2 h. Separate the layers. Extract the aqueous phase with 500 ml of DCM once. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 111.3 g of crude linagliptin.

[0066] Step 5: Recrystallization of linagliptin: Add 100 g of crude linagliptin to 1000 ml of isopropanol, heat to reflux, stir the system until clear, filter while hot, let the filtrate cool to room temperature naturally. During the cooling process, observe that solids precipitate. Keep stirring at a constant temperature for 2 h, filter, collect the filter cake, and dry it in a blast dryer at 50 °C to obtain 71.2 g of the finished linagliptin product, with a yield of 71.2% and a product purity > 99.5%.

[0067] Example 2

[0068] Step 1:

[0069]

[0070] Add 100.0 g of compound a, 98.4 g of compound b, 55.2 g of sodium carbonate, and 400 ml of N,N-dimethylformamide to the reaction flask in sequence. Control the temperature at 100 °C and stir for reaction. Monitor by TLC until compound a has basically reacted completely. Then cool to room temperature. Control the temperature at 20 - 30 °C and add 600 ml of water, stir to crystallize, filter, wash the filter cake with water, collect the filter cake, and dry it in a blast dryer at 60 °C for 16 h to obtain 132.3 g of compound c, with a yield of 88.6%.

[0071] Step 2:

[0072]

[0073] Add 127.5 g of compound c, 1300 ml of N,N-dimethylformamide, and 543 g of diisopropylethylamine to the reaction flask in sequence. Raise the internal temperature to 60 °C, control the temperature at 60 - 70 °C and dropwise add a DMF (130 ml) solution of 485.1 g of compound d. After addition, react at 70 °C for 1 h. Monitor by TLC until compound c has basically reacted completely. Cool the system to room temperature. Control the temperature at 20 - 30 °C and add 1450 ml of water. After addition, stir at 20 - 30 °C for 1 - 2 h, filter by suction. Wash the filter cake successively with 380 ml of solvent (DMF / H2O: 1 / 2) and 640 ml of H2O, collect the filter cake, and dry it in a blast dryer at 60 - 70 °C for 16 h to obtain 127.5 g of compound e, with a yield of 87.5%.

[0074] Step 3:

[0075]

[0076] Add 125.0 g of compound e, 606.8 g of compound f, 580.0 g of K2CO3, 9.7 g of tetrabutylammonium bromide, and 2500 ml of N,N-dimethylformamide into the reaction flask in sequence. Raise the internal temperature to 60 °C and react for 4 h. Monitor by TLC until compound e has basically reacted completely. Cool the system to room temperature. Control the temperature at 20 - 30 °C and add 3750 ml of water. After addition, cool the temperature to 5 - 15 °C and stir for 1 h while maintaining the temperature. Filter, and wash the filter cake successively with DMF / H2O = 1 / 1 and water to obtain the crude product;

[0077] Purification:

[0078] Add 2500 ml of DMF to the crude product. Raise the internal temperature to 80 °C and stir until it dissolves clearly. Then cool to room temperature. Control the temperature at 20 - 30 °C and add 3750 ml of water. After addition, cool the temperature to 5 - 15 °C and stir for 1 h while maintaining the temperature. Filter, and wash the filter cake successively with DMF / H2O = 1 / 1.2 and water. Collect the filter cake and dry it in a blast dryer at 70 °C to obtain 140.6 g of compound g, with a yield of 81.9%;

[0079] Step Four:

[0080]

[0081] Add 114.5 g of compound g, 860 ml of dichloromethane, and 114.5 ml of concentrated hydrochloric acid into the reaction flask in sequence. Control the temperature at 0 - 10 °C for reaction. Monitor by TLC until compound g has basically reacted completely. Dropwise add 1000 ml of 2M sodium hydroxide aqueous solution and stir for 24 hours. Separate the layers. Extract the aqueous phase once with 500 ml of DCM. Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and add ethanol for concentration to obtain 111.3 g of crude linagliptin.

[0082] Step Five: Recrystallization of Linagliptin: Add 100 g of crude linagliptin to 1000 ml of ethanol, heat to reflux, stir the system until it dissolves clearly, filter while it is hot. Let the filtrate cool naturally to room temperature. Observe that solids precipitate during the cooling process. Add 1000 ml of n-heptane, stir for 2 h while maintaining the temperature, filter, collect the filter cake, and dry it in a blast dryer at 50 °C to obtain 73.2 g of linagliptin finished product, with a yield of 73.2% and a product purity > 99.5%.

[0083] As Figure 1 shown, for the linagliptin API sample prepared according to the method of Example 1, its retention time is 22.759 min, and the result is as Figure 3 shown.

[0084] Its NMR data is as follows:

[0085] 1H-NMR (400 MHz, DMSO-d6) δ 8.26-8.23 (m, 1H), 7.93-7.89 (m, 1H), 7.82-7.80 (m, 1H), 7.69-7.65 (m, 1H), 5.32 (s, 2H), 4.90 (s, 2H), 3.73-3.58 (m, 2H), 3.40 (s, 3H), 3.04-2.97 (m, 1H), 2.88 (s, 3H), 2.86-2.82 (m, 1H), 1.89-1.85 (m, 1H), 1.81-1.78 (m, 1H), 1.77 (s, 3H), 1,67-1.61 (m, 1H), 1.28-1.19 (m, 1H).

[0086] Therefore, based on the above data results, it can be obtained that the high-purity linagliptin API can be obtained by using the preparation method of the present invention, which can effectively avoid the generation of dimer impurities, has simple operation, easily available materials, and is convenient for industrial production.

[0087] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variation thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or elements inherent to such process, method, article or device.

[0088] Although the embodiments of the present invention have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A preparation method of linagliptin, characterized in that, It includes the following steps: Step 1: Compound a reacts with compound b under alkaline conditions, at a certain temperature, in an organic solvent to form compound c, and the reaction is Step 2: Compound c reacts with compound d under alkaline conditions, at a certain temperature, in an organic solvent to form compound e, and the reaction is Step 3: Compound e reacts with compound f under alkaline conditions, at a certain temperature, in an organic solvent to form compound g, and the reaction is Step 4: Compound g undergoes deprotection by reaction under acidic conditions, at a certain temperature, in an organic solvent, and then depolymerizes under alkaline conditions to obtain the final linagliptin product, and the reaction is Step 5: The crude linagliptin obtained in Step 4 is subjected to cooling crystallization in an organic solvent at a certain temperature.

2. The preparation method of linagliptin according to claim 1, wherein: In Step 1, the molar ratio of the feed of compound a to compound b is n(b):n(a) = 1.0 to 1.

5.

3. The preparation method of linagliptin according to claim 1, characterized in that: In Step 2, the molar ratio of the feed of compound c to compound d is n(d):n(c) = 1.0 to 1.

5.

4. The preparation method of linagliptin according to claim 1, wherein: In Step 3, the molar ratio of the feed of compound e to compound f is n(f):n(e) = 1.0 to 2.

0.

5. The preparation method of linagliptin according to claim 1, characterized in that: The acidic conditions in Step 4 mean that the acid includes hydrochloric acid or trifluoroacetic acid, and the concentration of the hydrochloric acid solution is 2 mol / L to 12 mol / L.

6. The preparation method of linagliptin according to claim 1, characterized in that: The alkaline conditions in Step 4 refer to the base including one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, ammonia water, etc., or an aqueous solution of the above base, and the concentration of the aqueous solution of the base is 2 mol / L to 6 mol / L.

7. The preparation method of linagliptin according to claim 1, wherein: The alkaline conditions in Step 1, Step 2 and Step 3 refer to the base being an organic base or an inorganic base substance, including one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, diisopropylethylamine, triethylamine, etc.

8. A preparation method of linagliptin according to claim 1, characterized in that: The organic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, methanol, ethanol, acetonitrile, toluene, n-heptane or a mixture thereof, or a mixture of the above solvents and water.

9. The preparation method of linagliptin according to claim 1, wherein: The certain temperature in Step 1, Step 2 and Step 3 is 40°C to 140°C; The certain temperature in Step 4 and Step 5 is -10°C to 100°C.

10. A preparation method of linagliptin according to claim 1, characterized in that: The organic solvent in Step 5 is methanol, ethanol, isopropanol, tert-butanol, acetonitrile, n-heptane, ethyl acetate or a mixture thereof, or a mixture of the above solvents and water. For any of the preparation methods described above, the volume ratio of the anti-solvent to the solvent is 10:1 to 1:1; preferably 5:1 to 1:1.

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