Synthesis method of ticagrelor

Abstract

The invention relates to the field of organic synthesis, in particular to the field of organic drug synthesis, and more particularly relates to a synthesis method of ticagrelor, which changes the traditional synthesis thought and obtains the target product ticagrelor in a later docking mode. Meanwhile, by detecting the residual condition of the compound IV in the product and adjusting the adding amount of dibasic acid vinyl ester, the complete reaction can be ensured to the greatest extent, and the purification difficulty after the reaction is reduced. By adopting the synthesis thought and the synthesis method disclosed by the invention, the process is simple, the conditions are mild, the synthesis cost is lower compared with the synthesis method in the prior art, and the synthesis method is a novel synthesis method suitable for industrial popularization.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, in particular to the field of organic drug synthesis, and more specifically to a method for synthesizing ticagrelor. Background Art

[0002] Ticagrelor, whose chemical name is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, has a chemical structure as shown below: .

[0003] As an oral selective P2Y12 receptor inhibitor, ticagrelor has been widely recognized in the industry for its role in preventing ADP-mediated platelet activation and aggregation and reducing the probability of death from cardiovascular disease. Clinically, ticagrelor can significantly reduce the historical rate of acute coronary syndrome (ACS) and myocardial infarction (MI) in patients with myocardial infarction and stroke.

[0004] The methods for synthesizing ticagrelor in the prior art can be classified into two categories: One is to use compound a, compound b, compound c, and compound d as raw materials, and synthesize ticagrelor through steps such as amination, diazotization, and then halogenation. The synthesis route is as follows:

[0005] The other type is to change the structure of compound a to directly form a hydroxyethyl fragment at its hydroxyl group, thereby eliminating the need for compound c, and sequentially docking with compound b and compound d to form the target compound ticagrelor. The synthetic route is as follows: .

[0006] Both of the above methods have certain disadvantages: For example, in the first method, since it is necessary to first convert the halogen substitution into amino substitution and then into halogen substitution, the complexity of the process and the total yield of the product will inevitably increase. At the same time, methyl 2-(((trifluoromethyl)sulfonyl)oxy)acetate is used as a reagent for introducing hydroxyethyl in this synthesis step, the material cost is high, and the reaction yield is only 42%.

[0007] The second method changes the structure of compound a and directly uses a compound with a hydroxyethyl group as a raw material, thereby avoiding the use of methyl 2-(((trifluoromethyl)sulfonyl)oxy)acetate. However, in the subsequent reaction process, the hydroxyethyl group in the raw material is easily detached, resulting in the generation of a large amount of impurities. These impurities are difficult to purify and remove, and are transmitted through subsequent reactions, resulting in a high impurity content of the target compound in the final product, a low yield of the target compound, and the difficulty in separating these impurities from the target compound, which greatly affects the quality of the industrialized product of ticagrelor.

[0008] Therefore, researching and developing new ticagrelor synthesis routes has become the focus, difficulty and hot spot of research and development for technicians in the field of drug synthesis. Summary of the invention

[0009] The present invention aims to solve the problems of complex process and difficulty in removing impurities in the synthesis of ticagrelor in the prior art, and provides a new synthesis method of ticagrelor. In this method, compound IV is docked with dibasic acid vinyl ester to obtain compound V, and then docked with compound VI to obtain target compound VII (ticagrelor).

[0010] The present invention breaks away from the idea of ​​hydroxyethyl connection in the existing technology. By reacting the dibasic acid vinyl ester with compound IV, the oxygen heterocyclic ring can be opened while connecting the hydroxyethyl structural fragment, and the formation of three target substituents on the cyclopentane group in the target ticagrelor compound is simultaneously realized, and further docking with compound VI to form the target compound ticagrelor. The steps and process flow of ticagrelor synthesis are greatly simplified.

[0011] Further preferably, the dibasic acid vinyl ester is arbitrarily selected from one of vinyl carbonate, vinyl sulfate and vinyl sulfite.

[0012] Furthermore, the present invention also discloses that the compound IV reacts with dibasic acid vinyl ester in the presence of a base.

[0013] Preferably, the present invention further discloses that the base involved in the docking reaction of compound IV and dibasic acid vinyl ester is arbitrarily selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, triethylamine, and diisopropylamine; wherein, further preferably, the base is potassium tert-butoxide.

[0014] In a preferred technical solution, the molar ratio of the compound IV, the base and the dibasic acid vinyl ester is 1:(1-3):(1-2); wherein, a further preferred solution is that the molar ratio of the compound VI, the base and the dibasic acid vinyl ester is 1:1.2:1.2.

[0015] As a preferred technical solution, the present invention further discloses that the molar ratio of compound V to compound VI is 1:(1-1.2); wherein, further preferred is that the molar ratio of compound V to compound VI is 1:1.05.

[0016] At the same time, the present invention also discloses that compound V reacts with compound VI in the presence of an acid-binding agent, wherein the acid-binding agent is an organic base, and more preferably, the organic base is arbitrarily selected from one of triethylamine, diisopropylamine and dimethylamine.

[0017] As a preferred technical solution, the present invention further discloses a product detection step, i.e., detecting the content of compound IV in the reaction product of compound IV and dibasic acid vinyl ester, and adding dibasic acid vinyl ester according to the detection result until no residue of compound IV remains.

[0018] Of course, this process can be repeated to ensure that compound IV is completely reacted, thereby simplifying the subsequent purification difficulty.

[0019] Preferably, the detection method of the above compound IV adopts liquid phase detection method.

[0020] Furthermore, the present invention also discloses that the compound IV is obtained by using compound I and compound II as raw materials, obtaining compound III through docking reaction, and then further reacting with nitrite to construct a nitrogen heterocycle;

[0021] In the synthesis of compound IV, we directly selected amino as the pyrimidine ring substituent, which eliminates the need for an additional nitro reduction step. The synthesis process and procedure are simpler, and the product yield is high under this synthesis idea, meeting the needs of industrial promotion.

[0022] In a preferred technical solution, the molar ratio of compound I to compound II is 1:(1-1.5); wherein, more preferably, the molar ratio of compound I to compound II is 1:1.1.

[0023] At the same time, the present invention further discloses that the optimal reaction temperature for the reaction of compound I and compound II is 70-80°C.

[0024] Preferably, an organic base is required as an acid-binding agent during the reaction of compound I and compound II, and the organic base is arbitrarily selected from one of triethylamine, diisopropylamine and dimethylamine.

[0025] As a preferred technical solution, the molar ratio of compound III to nitrite is 1:(1-1.5); wherein it is further preferred that the molar ratio of compound III to nitrite is 1:1.05.

[0026] Preferably, the nitrite is one of sodium nitrite or potassium nitrite.

[0027] The present invention creatively provides a new idea for the synthesis of ticagrelor, which adopts a post-docking method to reduce impurities. At the same time, by detecting the remaining compound IV in the product and adjusting the amount of dibasic acid vinyl ester added, the reaction can be fully carried out to the greatest extent, reducing the difficulty of purification after the reaction.

[0028] The synthetic idea and synthetic method disclosed in the present invention not only have simple process but also mild conditions, and the synthetic cost is lower than that of the synthetic method in the prior art, and is a new synthetic method suitable for industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound VII obtained in Example 4. DETAILED DESCRIPTION

[0030] In order to better understand the present invention, the present invention is further described below in conjunction with specific embodiments.

[0031] Example 1 Synthesis of Compound III

[0032] Compound I (17.32 g, 0.1 mol), compound II (26.19 g, 0.11 mol), and ethanol (200 ml) were added to the reactor, and triethylamine (11.13 g, 0.11 mol) was added after stirring and mixing. The temperature was raised to 70-80°C and refluxed, and the reaction was stirred for 40 min.

[0033] Ethanol was completely distilled off under reduced pressure, ethyl acetate (200 ml) and water (200 ml) were added to the residue, stirred and separated, and the organic phase was washed once more with water.

[0034] The organic phase was decompressed and dried ethyl acetate was recovered to obtain compound III (32.5 g, 0.0867 mol) with a yield of 86.7%.

[0035] Example 2 Synthesis of Compound IV

[0036] Add compound III (37.49 g, 0.1 mol), acetic acid (9 g, 0.15 mol) and water (100 ml) into the reactor and stir until completely dissolved. Then slowly add sodium nitrite aqueous solution (7.24 g, 0.105 mol, 50 ml) dropwise. The addition should be completed within 20 min. Cool down to 0-5 °C and stir to react for 20 min.

[0037] Excess acetic acid was distilled off under reduced pressure, ethyl acetate (200 ml) and water (200 ml) were added to the residue, stirred and separated, and the organic phase was washed once more with water.

[0038] The organic layer was dried and the solvent was recovered under reduced pressure, and the residue was collected to obtain compound IV (33.96 g, 0.088 mol) with a yield of 88%.

[0039] Example 3 Synthesis of Compound V

[0040] Add compound IV (38.59 g, 0.1 mol) and ethylene carbonate (10.57 g, 0.12 mol) into the reactor, then add tetrahydrofuran (200 ml) and stir until dissolved, add potassium tert-butoxide (13.47 g, 0.12 mol), raise the temperature to 30-35 °C, react for 2 h, then add 98% concentrated sulfuric acid (20.02 g, 0.2 mol) and stir for 0.5 min.

[0041] After the reaction was completed, the dry solvent was recovered under reduced pressure, and the residue was collected. After testing, the product was compound V (36.16 g, 0.084.1 mol), with a liquid phase purity of 99.6% and a yield of 84.1%.

[0042] Example 4 Synthesis of Compound VII

[0043] Compound V (42.99 g, 0.1 mol), compound VI (17.76 g, 0.105 mol) and acetonitrile (250 ml) were added into the reactor and stirred to mix. Then triethylamine (11.13 g, 0.11 mol) was added and the temperature was raised to 30-40°C and stirred to react for 15 h.

[0044] The dry acetonitrile was recovered under reduced pressure, ethyl acetate (250 ml) and water (200 ml) were added to the residue, stirred and separated, and the organic phase was washed once more with water.

[0045] The organic phase was decompressed and dried ethyl acetate was recovered to obtain compound VII (45.93 g, 0.0879 mol) with a yield of 87.9% and a liquid phase purity of 99.5%. The H NMR spectrum showed Figure 1 . Embodiment 5~7

[0046] Other conditions were the same as those in Example 1, except for the molar ratio of compound I to compound II and the type of organic base. The reaction conditions and yields of Example 1 and Examples 5-7 are detailed in Table 1.

[0047] Table 1 Different conditions and results of Example 1 and Examples 5-7 Example Compound I: Compound II Types of alkali Yield / % 1 1:1.1 Triethylamine 86.7 5 1:1 Triethylamine 86.2 6 1:1.5 Triethylamine 86.4 7 1:1.1 Diisopropylamine 85.8 Embodiments 8 to 10

[0048] Other conditions were the same as those in Example 2, except that the molar ratio of compound III to nitrite was changed; the type of nitrite, reaction conditions and yields of Example 2 and Examples 8-10 are detailed in Table 2.

[0049] Table 2 Different conditions and results of Example 2, Example 8-10 Example Compound III: Nitrite Types of Nitrite Yield / % 2 1:1.05 Sodium Nitrite 88 8 1:1 Sodium Nitrite 86.6 9 1:1.5 Sodium Nitrite 87.4 10 1:1.05 Potassium Nitrite 87.8 Embodiments 11 to 14

[0050] The other conditions are the same as those in Example 3, except that the molar ratio of compound IV, base and dibasic acid vinyl ester is changed; the type of base and the type of dibasic acid vinyl ester, the reaction conditions and results of Example 3 and Examples 11-14 are detailed in Table 3.

[0051] Table 3 Different conditions and results of Example 3 and Examples 11-14 Example Compound IV: Base: Vinyl dibasic acid ester Types of alkali Types of vinyl esters Yield / % 3 1:1.2:1.2 Potassium tert-butoxide Ethylene carbonate 84.1 11 1:1:1 Potassium tert-butoxide Ethylene carbonate 83.1 12 1:3:2 Potassium tert-butoxide Ethylene carbonate 83.6 13 1:1.2:1.2 Potassium carbonate Ethylene carbonate 81.8 14 1:1.2:1.2 Potassium tert-butoxide Vinyl Sulfate 82.9 Embodiments 15 to 17

[0052] Other conditions were the same as those in Example 4, except that the molar ratio of Compound V to Compound VI was changed; the type of organic base used as the acid-binding agent, the reaction conditions and yields of Example 4 and Examples 15-17 are detailed in Table 4.

[0053] Table 4 Different conditions and results of Example 4 and Examples 15-17 Example Compound V: Compound VI Types of alkali Yield / % 4 1:1.05 Triethylamine 87.9 15 1:1 Triethylamine 87.2 16 1:1.2 Triethylamine 87 17 1:1.05 Diisopropylamine 86.3 It can be seen that the post-docking synthesis route disclosed in the present invention provides a new synthesis idea and method for the synthesis of ticagrelor. Using the synthesis route disclosed in the present invention, not only the synthesis process is simpler, but also the synthesis conditions are milder and the cost is lower.

[0054] When the preferred process conditions disclosed in the present invention are selected, the yield is higher and the effect is better.

[0055] The above is a specific implementation of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications are also considered to be within the protection scope of the present invention.

Claims

1. A method for synthesizing ticagrelor, characterized in that: This method docks compound IV with dibasic acid vinyl ester to obtain compound V, and then docks it with compound VI to obtain target compound VII (ticagrelor); 2. The method for synthesizing ticagrelor according to claim 1, characterized in that: The dibasic acid vinyl ester is arbitrarily selected from one of vinyl carbonate, vinyl sulfate and vinyl sulfite.

3. The method for synthesizing ticagrelor according to claim 1, characterized in that: The compound IV reacts with the dibasic acid vinyl ester in the presence of a base. Preferably, the base involved in the docking reaction between the compound IV and the dibasic acid vinyl ester is arbitrarily selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, triethylamine, and diisopropylamine; wherein, more preferably, the base is potassium tert-butoxide; Further preferably, the molar ratio of the compound IV, the base and the dibasic acid vinyl ester is 1:(1-3):(1-2); wherein, a further preferred scheme is that the molar ratio of the compound VI, the base and the dibasic acid vinyl ester is 1:1.2:1.

2.

4. The method for synthesizing ticagrelor according to claim 1, characterized in that: The molar ratio of compound V to compound VI is 1:(1-1.2); wherein, more preferably, the molar ratio of compound V to compound VI is 1:1.

05.

5. The method for synthesizing ticagrelor according to claim 1, characterized in that: Compound V reacts with compound VI in the presence of an acid-binding agent, wherein the acid-binding agent is an organic base. More preferably, the organic base is arbitrarily selected from one of triethylamine, diisopropylamine and dimethylamine.

6. The method for synthesizing ticagrelor according to claim 1, characterized in that: The method further comprises a product detection step, in which the content of compound IV is detected in the reaction product of compound IV and dibasic acid vinyl ester, and based on the detection result, dibasic acid vinyl ester is added until no residue of compound IV remains; preferably, a liquid phase detection method is adopted.

7. The method for synthesizing ticagrelor according to claim 1, characterized in that: The compound IV is obtained by using compound I and compound II as raw materials, obtaining compound III through docking reaction, and then further reacting with nitrite to construct a nitrogen heterocycle; 8. The method for synthesizing ticagrelor according to claim 7, characterized in that: The mixing molar ratio of the raw materials in each step is preferably: The molar ratio of compound I to compound II is 1:(1-1.5); more preferably, the molar ratio of compound I to compound II is 1:1.1; The molar ratio of compound III to nitrite is 1:(1-1.5); wherein it is further preferred that the molar ratio of compound III to nitrite is 1:1.

05.

9. The method for synthesizing ticagrelor according to claim 7, characterized in that: An organic base is required as an acid-binding agent during the reaction of compound I and compound II, and the organic base is arbitrarily selected from one of triethylamine, diisopropylamine and dimethylamine.

10. The method for synthesizing ticagrelor according to claim 7, characterized in that: Any one or more of the following conditions are preferred: (1) The optimal reaction temperature for the reaction of compound I and compound II is 70-80°C; (2) The nitrite is selected from sodium nitrite or potassium nitrite.

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