Preparation method of ticagrelor
Through the docking of compound V with IV and reaction of vinyl dibasic acid, the synthesis route of ticagrel is simplified, and the problems of many steps, complex processes and low yields in the existing technology are solved, and high purity and high yields are achieved. Production of target compounds, suitable for industrial applications.
Patent Information
- Application Number
- CN202411411438.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-10
- Publication Date
- 2025-01-17
AI Technical Summary
The existing ticagre synthesis route has many steps, complex processes, high material costs and low synthesis yield, making it difficult to meet the needs of industrial production.
Compound V is used to dock with compound IV, and then react with dibasic acid vinyl ester to directly obtain the target compound ticagrel, simplify the synthesis steps, skip the original ammonization and diazotide halogenation operations, and control the reaction with N protecting groups. Improve impurity generation and purity.
It significantly simplifies the synthesis steps, improves product yield, reduces process costs, is suitable for industrial promotion, and meets the production needs of high purity and high yield.
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Figure CN119320391A_ABST
Abstract
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 preparing 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 in formula (A): .
[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 original research company of ticagrelor disclosed a method for preparing ticagrelor, and its synthesis route is as follows: .
[0005] In this synthetic route, the chlorine substituent in compound e is first converted to an amino group to form compound f, which is then docked with methyl 2-(((trifluoromethyl)sulfonyl)oxy)acetate to form compound g, and then undergoes a diazotization bromination reaction to form compound h, thereby further obtaining the target product ticagrelor (compound j).
[0006] This synthetic route has the following disadvantages: First, in this synthetic route, halogen substitution is first converted to amino substitution and then to halogen substitution, which has many steps and a complicated process; Second, the use of methyl 2-(((trifluoromethyl)sulfonyl)oxy)acetate as a reagent for introducing hydroxyethyl groups results in high material costs; Third, the yields of synthesizing compound g from compound f and further synthesizing compound h from compound g are both very low, among which the yield of synthesizing compound g from compound f is only 42%.
[0007] Therefore, researching and developing new synthetic routes and providing new preparation methods have become the focus and hotspot of research and development for technicians in the field of ticagrelor drug synthesis. Summary of the invention
[0008] In view of the problems of multiple steps, complex process and low synthesis yield in the existing ticagrelor synthesis, the present invention discloses a novel preparation method of ticagrelor, wherein compound V and compound IV are docked to form compound VI; compound VI is then reacted with dibasic acid vinyl ester to directly obtain the target compound ticagrelor (compound VII).
[0009] Wherein, M is arbitrarily selected from tert-butyloxycarbonyl, benzyl ester, benzylsulfonyl, p-toluenesulfonyl, methylsulfonyl, Trt, Bn, Pmb, Dmb, and more preferably, M is tert-butyloxycarbonyl.
[0010] In the preparation method disclosed in the present invention, it can be seen that on the basis of compound IV, we changed the original method of first docking with 2-(((trifluoromethyl)sulfonyl)oxy)acetic acid methyl ester, then docking with 1-aminocyclopropane-3,4-difluorobenzene, and then reducing to form the final ticagrelor with a hydroxyethyl structural fragment. By creatively utilizing compound V, compound VI with an amino protecting group is formed, and on this basis, it is directly reacted with dibasic acid vinyl ester to simultaneously achieve the purpose of deprotection, connecting the target fragment hydroxyethyl and opening the oxygen heterocycle to form a hydroxyl group. This preparation method greatly simplifies the synthesis steps while ensuring the purity and yield of the product.
[0011] Preferably, the dibasic acid vinyl ester is arbitrarily selected from vinyl carbonate, vinyl sulfate, and vinyl sulfite.
[0012] More preferably, the molar ratio of compound IV to compound V is 1:(1-1.2).
[0013] In a preferred technical solution, the molar ratio of compound IV to compound V is 1:1.05.
[0014] More preferably, the compound IV reacts with the compound V in the presence of an acid-binding organic base.
[0015] Preferably, the organic base is arbitrarily selected from triethylamine, diisopropylamine or dimethylamine.
[0016] Preferably, the compound VI reacts with the vinyl dibasic acid ester in the presence of a base, wherein the base includes but is not limited to one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, triethylamine, and diisopropylamine; further preferably, the base is potassium tert-butoxide.
[0017] More preferably, the molar ratio of compound VI, base and dibasic acid vinyl ester is 1:(1-3):(1-2).
[0018] In a preferred technical solution, the molar ratio of compound VI, base and dibasic acid vinyl ester is 1:1.2:1.2.
[0019] As a preferred technical solution, the present invention further discloses that the compound IV is prepared from compound I and compound II as raw materials, and after a docking reaction to obtain compound III, the compound III is further reacted with nitrite to construct a nitrogen heterocycle;
[0020] Compared with the preparation method of ticagrelor-related steps disclosed in the original patent, the synthesis route disclosed in the present invention does not require the reduction of the nitro group, the synthesis process is simpler, and according to experimental data, it can be seen that the yield of the synthesis is relatively high and can meet the needs of industrial synthesis.
[0021] Preferably, the molar ratio of compound I to compound II is 1:(1-1.5).
[0022] In a preferred technical solution, the molar ratio of compound I to compound II is 1:1.1.
[0023] As a preferred technical solution, the reaction temperature of compound I and compound II is preferably 70-80°C.
[0024] Preferably, the compound I reacts with the compound II in the presence of an acid-binding organic base, wherein the organic base is 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).
[0026] More preferably, the molar ratio of compound III to nitrite is 1:1.05.
[0027] Wherein, the nitrite is arbitrarily selected from sodium nitrite and potassium nitrite.
[0028] The present invention does not require repeated operations such as amination, diazotization and re-halogenation, and creatively involves an N protecting group in compound V, so that it can be directly docked with compound IV, and can significantly control the generation of impurities during the docking process, thereby greatly improving production efficiency and reaction yield.
[0029] At the same time, the present invention uses dibasic acid vinyl ester as a reagent for introducing hydroxyethyl, jumps out of the original synthesis idea, makes the process simpler, the cost lower, and the yield higher. The preparation method disclosed by the present invention is a new synthesis method with simpler synthesis process, milder synthesis conditions, lower synthesis cost, and suitable for industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound VI prepared in Example 3.
[0031] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound VII prepared in Example 4. DETAILED DESCRIPTION
[0032] In order to better understand the present invention, the present invention is further described below in conjunction with specific embodiments.
[0033] Example 1 Synthesis of Compound III
[0034] 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.
[0035] The ethanol was completely distilled off under reduced pressure, ethyl acetate (200 ml) and water (200 ml) were added to the residue, the mixture was stirred to separate the liquids, and the organic phase was washed once more with water.
[0036] 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%.
[0037] Example 2 Synthesis of Compound IV
[0038] 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 and control the addition to be completed within 20 min. Cool to 0~5 °C and stir to react for 20 min.
[0039] Excess acetic acid was distilled off under reduced pressure, ethyl acetate (200 ml) and water (200 ml) were added to the residue, stirred and the liquid was separated, and the organic phase was washed once more with water.
[0040] 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%.
[0041] Example 3 Synthesis of Compound VI
[0042] Add compound IV (38.59 g, 0.1 mol), compound V (27.28 g, 0.105 mol) and acetonitrile (250 ml) into the reactor and stir to mix. Then add triethylamine (11.13 g, 0.11 mol) and heat to 30-40 °C. Stir and react for 15 h.
[0043] 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.
[0044] The organic phase was recovered to dryness under reduced pressure, and ethyl acetate was collected to obtain the product (54.07 g, 0.0874 mol). Figure 1 The H NMR spectrum shown confirmed that the product was compound VI, and the calculated yield of compound VI was 87.4%.
[0045] Example 4 Synthesis of Compound VII
[0046] Add compound VI (61.87 g, 0.1 mol) and ethylene carbonate (10.57 g, 0.12 mol) to the reactor, then add tetrahydrofuran (250 ml), stir until dissolved, add potassium tert-butoxide (13.47 g, 0.12 mol), heat to 30-35 °C, react for 2 h, then add 98% concentrated sulfuric acid (20.02 g, 0.2 mol), stir and react for 0.5 min.
[0047] After the reaction was completed, the solvent was recovered under reduced pressure, the residue was collected, and the product was sent for inspection. Figure 2 The H NMR spectrum shown above confirmed that the product was the target compound VII (43.58 g, 0.0834 mol), and the calculated yield of compound VII was 83.4%. Embodiment 5~7
[0048] Other conditions were the same as those in Example 1, except that the reaction molar ratio of compound I to compound II was changed; or the type of organic base was changed to construct Examples 5-7 respectively. The reaction conditions and yields of Examples 1 and 5-7 are shown in Table 1 for details.
[0049] 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 Embodiment 8-10
[0050] Other conditions were the same as those in Example 2, except that the molar ratio of compound III to nitrite or the type of nitrite was changed. The reaction conditions and yields of Example 2 and Examples 8-10 are detailed in Table 2.
[0051] 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
[0052] Other conditions were the same as those in Example 3, except that the molar ratio of compound IV to compound V, or the type of organic base, and the type of M protecting group were changed. The reaction conditions and yields of Example 3 and Examples 11-14 are detailed in Table 3.
[0053] Table 3 Different conditions and results of Example 3 and Examples 11-14 Example Compound IV: Compound V Types of alkali M Yield / % 3 1:1.05 Triethylamine Boc 87.4 11 1:1 Triethylamine Boc 86.9 12 1:1.2 Triethylamine Boc 86.8 13 1:1.05 Diisopropylamine Boc 86.1 14 1:1.05 Triethylamine Trt 87.1 Embodiments 15 to 19
[0054] Other conditions are the same as those in Example 4, except that the molar ratio of compound VI, base and dibasic acid vinyl ester is changed; or the type of base, or the type of dibasic acid vinyl ester; or the type of M protecting group is changed. The reaction conditions and results of Example 4 and Examples 15-19 are detailed in Table 4.
[0055] Table 4 Different conditions and results of Example 4 and Examples 15-19 Example Compound VI: Base: dibasic acid vinyl ester Types of alkali Types of vinyl esters M Yield / % 4 1:1.2:1.2 Potassium tert-butoxide Ethylene carbonate Boc 83.4 15 1:1:1 Potassium tert-butoxide Ethylene carbonate Boc 82.3 16 1:3:2 Potassium tert-butoxide Ethylene carbonate Boc 82.7 17 1:1.2:1.2 Potassium carbonate Ethylene carbonate Boc 81.1 18 1:1.2:1.2 Potassium tert-butoxide Vinyl Sulfate Boc 82.5 19 1:1.2:1.2 Potassium tert-butoxide Ethylene carbonate Trt 82.8 It can be seen from this that the creative core of the present invention lies in the disclosure of a new synthetic route. Through the synthetic route disclosed by the present invention, there is no need to repeat multiple steps such as amination, diazotization and then halogenation. After the creative introduction of the N protecting group, the target compound can be obtained with high yield and high purity. Under the premise of ensuring the reaction purity, the reaction yield is effectively improved, the process steps are reduced, and it is more in line with the requirements of industrial production.
[0056] When the preferred process conditions disclosed in the present invention are selected, the yield is higher and the effect is better.
[0057] 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 preparing ticagrelor, characterized in that: The method docks compound V with compound IV to form compound VI; then compound VI reacts with dibasic acid vinyl ester to directly obtain the target compound ticagrelor (compound VII). Wherein, M is arbitrarily selected from tert-butyloxycarbonyl, benzyl ester, benzylsulfonyl, p-toluenesulfonyl, methylsulfonyl, Trt, Bn, Pmb, Dmb, and more preferably, M is tert-butyloxycarbonyl.
2. The method for preparing ticagrelor according to claim 1, characterized in that: The dibasic acid vinyl ester is arbitrarily selected from vinyl carbonate, vinyl sulfate, and vinyl sulfite.
3. The method for preparing ticagrelor according to claim 1, characterized in that: The molar ratio of compound IV to compound V is 1:(1-1.2); Among them, the most preferred is that the molar ratio of compound IV to compound V is 1:1.05 4. The method for preparing ticagrelor according to claim 1, characterized in that: The compound IV reacts with the compound V in the presence of an acid-binding organic base.
5. The method for preparing ticagrelor according to claim 4, characterized in that: The organic base is arbitrarily selected from one of triethylamine, diisopropylamine or dimethylamine.
6. The method for preparing ticagrelor according to claim 1, characterized in that: Compound VI is reacted with a dibasic acid vinyl ester in the presence of a base.
7. The method for preparing ticagrelor according to claim 6, characterized in that the reaction The reaction molar ratio of compound VI, base and dibasic acid vinyl ester is 1:(1-3):(1-2); Among them, the most preferred reaction molar ratio of compound VI, base and dibasic acid vinyl ester is 1:1.2:1.
2.
8. The method for preparing ticagrelor according to claim 6 or 7, characterized in that: The base 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; further preferably, the base is potassium tert-butoxide.
9. The method for preparing ticagrelor according to claim 1, characterized in that the compound IV is prepared from compound I and compound II as raw materials, and compound III is obtained by docking reaction, and then further reacted with nitrite to construct a nitrogen heterocycle; 10. The method for preparing ticagrelor according to claim 9, characterized in that: Arbitrarily select any one or several non-conflicting reaction conditions from the following: a. The molar ratio of compound I to compound II is 1:(1-1.5); b. The molar ratio of compound I to compound II is 1:1.1; c. The reaction temperature of compound I and compound II is 70-80°C; d. The compound I reacts with the compound II in the presence of an acid-binding organic base; wherein, further preferably, the organic base is selected from one of triethylamine, diisopropylamine and dimethylamine; e. The molar ratio of compound III to nitrite is 1:(1-1.5); further preferably, the molar ratio of compound III to nitrite is 1:1.05; f. The nitrite is arbitrarily selected from sodium nitrite and potassium nitrite.