Ticagrelor intermediate, preparation method therefor and synthesis method using said intermediate

Abstract

The present invention relates to the field of organic synthesis, especially to the field of organic drug synthesis, and more specifically to a ticagrelor intermediate, a preparation method therefor and a synthesis method using said intermediate. Using the ticagrelor intermediate can not only reduce synthesis steps, simplify the synthesis process and greatly shorten synthesis time, but also does not require the use of sodium borohydride and palladium / carbon, lowering costs and improving safety, which facilitates industrial use and promotion. In addition, in a subsequent process using the ticagrelor intermediate, a target group is synthesized by means of etherification without ester group reduction, and in a subsequent deprotection process, an active amine is used to effectively prevent inorganic salt residues, and a ticagrelor intermediate compound C can be obtained without washing and extraction. This not only makes the process simpler, but also greatly reduces labor costs, production costs and post-processing costs, and is suitable for industrial production use and promotion.

Description

Ticagrelor intermediate, preparation method thereof, and synthesis method using the intermediate 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 ticagrelor intermediate and a preparation method thereof, and a synthesis method using the intermediate. Background Art

[0002] Ticagrelor is an oral, selective P2Y12 receptor inhibitor that prevents ADP-mediated platelet activation and aggregation, and can reduce the incidence of cardiovascular death, acute coronary syndrome (ACS) and myocardial infarction (MI) in patients with myocardial infarction and stroke.

[0003] The chemical name of ticagrelor 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, and its chemical structure is as follows:

[0004] The five-membered ring compound C is an important intermediate compound in the synthesis of ticagrelor. It is linked with two other important intermediates, compound A (pyrimidine ring) and compound C (three-membered ring), to form the target product ticagrelor.

[0005] Among them, compound C has multiple chiral centers, and its synthesis route and preparation method have always been a hot topic and difficulty for those skilled in the art.

[0006] For example, the preparation method of this intermediate is reported in patent US7067663.

[0007] This solution requires the use of expensive lithium borohydride and palladium carbon, and the entire preparation process is costly. At the same time, this solution has disadvantages such as many process steps, difficult process operation, and low yield.

[0008] For example, WO2011017108A also discloses a method for preparing a ticagrelor intermediate, and its synthetic route is as follows:

[0009] This synthetic route uses D-alanine as the starting material and, through a series of reactions, yields an intermediate compound bearing a -Cbz protecting group. This reaction is not only lengthy and multi-step, but also requires the use of sodium borohydride in the seventh step to reduce the substituted -N on the ring. This is followed by further catalytic reduction using palladium on carbon in the eighth step to yield the NH—O ring-opened compound.

[0010] For those skilled in the art, sodium borohydride and palladium carbon are not ideal. First, sodium borohydride is a strong irritant that can produce a strong irritation to mucous membranes, upper respiratory tract, eyes and skin. After inhalation, it can cause spasm, inflammation, and edema in the larynx and bronchus, and then may cause chemical pneumonia and pulmonary edema, resulting in a risk of death. In addition, sodium borohydride itself is unstable and has potential safety hazards. It is not suitable for industrial production as a raw material and is widely used. Secondly, the cost of palladium carbon is high, and it is difficult to recycle, which causes the synthesis production cost to increase, and is therefore not suitable for industrial production. It can be seen at the same time that in the scheme disclosed in the document, the seventh step reaction time is 50 minutes, and it is necessary to repeatedly adjust the pH to obtain the product. On the basis of the seventh step product, the eighth step ring-opening reaction time needs 60 minutes, and the whole process is not only time-consuming, but also complex.

[0011] In summary, developing a new synthesis method for compound C, an important intermediate of ticagrelor, has always been a key research and development direction for those skilled in the art and is also a hot topic in research in this field.

[0012] Summary of the Invention

[0013] The technical problem to be solved by the present invention is to provide a new method for synthesizing the important intermediate compound C of ticagrelor, thereby solving the problems existing in the existing synthesis, such as long route, multiple steps, high cost, low safety and high toxicity.

[0014] In order to solve the above technical problems, the present invention discloses a new ticagrelor intermediate, whose structural formula is shown in Formula 2:

[0015] wherein R1 is arbitrarily selected from alkyl acid ions and sulfonate ions.

[0016] Furthermore, the present invention also discloses a method for preparing a ticagrelor intermediate compound 2, wherein the compound 2 is obtained by reacting the compound 1 with hydrogen and an organic acid in the presence of Raney nickel;

[0017] wherein K is a substituted or unsubstituted benzyl group.

[0018] Furthermore, the preparation method of compound 2 includes the following steps: (1) adding compound 1, Raney nickel, molybdenum powder, organic acid and solvent into a reactor and stirring; (2) replacing the air in the system with nitrogen; (3) introducing hydrogen and pressurizing; (4) heating to 75-80°C and reacting; (5) after the reaction is completed, filtering to remove the Raney nickel, and concentrating the filtrate to dryness under reduced pressure to obtain compound 2.

[0019] Preferably, the molar ratio of the compound 1 to the organic acid is 1:1 to 1.2.

[0020] Preferably, the organic acid is selected from any one of acetic acid, p-toluenesulfonic acid or pivalic acid, and particularly preferably, the organic acid is pivalic acid. Correspondingly, R1 is an acetate ion, a p-toluenesulfonic acid ion or a pivalate ion, respectively.

[0021] Preferably, the solvent is an alcohol solvent. In a preferred technical solution, the solvent is methanol.

[0022] Furthermore, the present invention also discloses a method for preparing a ticagrelor intermediate compound C using compound 2, wherein the compound 2 is reacted with an acid anhydride to prepare compound 3, and then the ticagrelor intermediate compound C is further prepared;

[0023] Wherein, R1 is arbitrarily and independently selected from one of C1-C5 alkyl, H, aryl and substituted aryl; R2 is arbitrarily and independently selected from one of C1-C5 alkyl, aryl and substituted aryl.

[0024] Preferably, the acid anhydride is one of acetic anhydride, succinic anhydride and phthalic anhydride.

[0025] Furthermore, the present invention also discloses a method for further preparing the compound 3 to obtain the intermediate compound C of ticagrelor, comprising the following steps:

[0026] (a) Compound 3 reacts with an etherification agent to form compound 4;

[0027] (b) Compound 4 reacts with an active amine compound to obtain Compound 5 (Compound C).

[0028] Preferably, the etherifying agent is selected from one of ethylene carbonate, ethylene sulfate, and ethylene sulfite, preferably ethylene carbonate; preferably, the molar ratio of compound 3 to the etherifying agent is 1:1-2; preferably, the reaction temperature of step (a) is 30-35°C.

[0029] Preferably, the active amine is dimethylamine or n-butylamine.

[0030] More preferably, the molar ratio of compound 4 to active amine is 1:1-2.

[0031] Furthermore, the present invention also discloses that compound 6 is prepared by reacting compound 5 with tartaric acid.

[0032] In a preferred technical solution, the molar ratio of compound 5 to tartaric acid is 1:1-2, preferably 1:1.2;

[0033] In a preferred technical solution, the reaction temperature of compound 5 and tartaric acid is 40-55°C, and further, the crystallization temperature is 5-20°C.

[0034] The present invention discloses a new synthetic ticagrelor intermediate. The use of the ticagrelor intermediate can not only reduce the number of synthesis steps, simplify the synthesis process, and greatly shorten the synthesis time; but also does not require the use of sodium borohydride and palladium carbon, which has lower costs and higher safety, and is conducive to industrial use and promotion. The inventors of the present invention unexpectedly discovered that by using Raney nickel, not only can the process be simplified, but the synthesis time can also be effectively shortened. In particular, the inventors of the present invention creatively discovered that by adding an organic acid, the reaction time can be further significantly shortened, resulting in unexpected technical effects. In addition, in the subsequent process of applying the ticagrelor intermediate, the target group is synthesized by etherification without the need for ester group reduction. In the subsequent deprotection process, the active amine is used to effectively avoid inorganic salt residues, and the ticagrelor intermediate compound C can be obtained without washing and extraction, which not only makes the process simpler, but also greatly reduces labor costs, production costs and post-processing costs, making it suitable for industrial production application and promotion. DETAILED DESCRIPTION

[0035] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0036] Example 1 Synthesis of Compound 2

[0037] Compound 1 (0.1 mol, 26.13 g), Raney nickel (6.5 g), molybdenum powder (0.06 g), pivalic acid (0.11 mol, 11.29 g), and methanol (260 ml) were added to the reactor and stirred until the system became turbid. The air was replaced with nitrogen twice, and hydrogen was introduced and pressurized to 1.0 MPa. The temperature was raised to 75-80°C and the reaction was completed after 8 hours of reaction.

[0038] After the reaction was completed, the Raney nickel was filtered off, the filter cake was washed with methanol, and the methanol phases were combined. The methanol was dried under reduced pressure to obtain a light yellow solid, compound 2 (0.0981 mol, 27.01 g), with a yield of 98.1%.

[0039] Example 2 Synthesis of Compound 3

[0040] Compound 2 (27.54 g, 0.1 mol) and dichloromethane (250 ml) were added to the reactor, stirred to dissolve, and then cooled to 0-10°C. Acetic anhydride (10.72 g, 0.105 mol) was added dropwise to the system at a temperature of 0-10°C over 30 minutes, and the reaction was continued at this temperature for 2 hours.

[0041] After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 7-8. The organic layer was separated by standing. The solvent was completely distilled under reduced pressure. The residue was collected to obtain compound 3 (20.17 g, 0.0937 mol) with a yield of 93.7%.

[0042] Example 3 Synthesis of Compound 4

[0043] Compound 3 (30 g, 0.14 mol) and ethylene carbonate (14.8 g, 0.168 mol) were added to the reactor, and then tetrahydrofuran (150 ml) was added and stirred until dissolved. Potassium tert-butoxide (112.2 g, 0.168 mol) was added, and the temperature was raised to 30-35°C. The reaction was continued for 2 h, and concentrated sulfuric acid (2.8 g, 0.028 mol) was added and stirred for 0.5 min.

[0044] After the reaction was completed, the solvent was recovered under reduced pressure and the residue was collected to obtain compound 4 (31.4 g, 0.121 mol) with a yield of 85.9%.

[0045] Example 4 Synthesis of Compound 5

[0046] Compound 4 (25.9 g, 0.1 mol) was added to the reactor, and ethanol (200 ml) was added and stirred. Dimethylamine (6.76 g, 0.15 mol) was added dropwise. The temperature was raised to 40-50° C. and the reaction was carried out at this temperature for 16 h.

[0047] After the reaction was completed, the dry solvent was recovered under reduced pressure to obtain compound 5 (19.99 g, 0.092 mol) with a yield of 92%.

[0048] Example 5 Synthesis of Compound 6

[0049] Add compound 5 (15.2 g, 0.07 mol) and ethanol (100 ml) to the reactor and stir until completely dissolved. Heat the system to 45-50°C. Begin by adding tartaric acid in three evenly distributed batches, with 5-minute intervals between each batch. Add a total of tartaric acid (12.6 g, 0.084 mol). Maintain the temperature at 45-50°C and stir for 1 hour.

[0050] After the reaction is completed, slowly cool down to 30-40°C. When the temperature reaches 30°C, further cool down the system. Solids will gradually precipitate. Cool the system to 10-15°C and stir for crystallization for 10-12 hours.

[0051] After crystallization, centrifuge and rinse the filter cake twice with cold ethanol (30 ml);

[0052] After centrifugation, the wet product was transferred to a vacuum oven at 40-50° C. and dried to obtain compound 6 (22.86 g, 0.0622 mol) with a yield of 88.9% and a liquid phase purity of 99.6%.

[0053] Comparative Example 1 Synthesis of Compound 2

[0054] Compound 1 (0.1 mol, 26.13 g), Raney nickel (6.5 g), molybdenum powder (0.06 g), and methanol (260 ml) were added to the reactor and stirred until the system became turbid. The air was replaced with nitrogen twice, and hydrogen was introduced and pressurized to 1.0 MPa. The temperature was raised to 75-80°C and the reaction was completed for 24 hours.

[0055] After the reaction was completed, the Raney nickel was filtered off, the filter cake was washed with methanol, and the methanol phases were combined. The methanol was dried under reduced pressure to obtain a light yellow solid (0.0968 mol, 16.77 g) with a yield of 96.8%.

[0056] Comparative Example 2 Synthesis of Compound 5

[0057] Compound 4 (25.9 g, 0.1 mol) was added to the reactor, and ethanol (200 ml) was added and stirred. 100 ml of potassium carbonate aqueous solution (41.5 g potassium carbonate, 3 mol / L potassium carbonate concentration) was added dropwise. The temperature was raised to 40-50°C and the reaction was kept warm for 16 h.

[0058] After the reaction, the ethanol in the dry system was recovered under reduced pressure, and ethyl acetate (200 ml) was added for extraction twice. The organic layers were combined, dried, and the solvent was evaporated to obtain compound 5 (19.9 g, 0.0916 mol) with a yield of 91.6%.

[0059] Examples 6 to 8

[0060] Other conditions were the same as those in Example 1, except for the molar ratio of Compound 1 to the organic acid and the type of the organic acid. The reaction conditions and yields of Example 1 and Examples 6-8 are detailed in Table 1.

[0061] Table 1 Different conditions and results of Example 1 and Examples 6-8

[0062] Examples 9-11

[0063] Other conditions were the same as those in Example 2, except for the molar ratio of compound 2 to acid anhydride and the type of acid anhydride. The reaction conditions and yields of Example 2 and Examples 9-11 are detailed in Table 2.

[0064] Table 2 Different conditions and results of Example 2 and Examples 9-11

[0065] Examples 12 to 14

[0066] Other conditions were the same as those in Example 3, except that the molar ratio of compound 3 to the etherification agent was changed; the type of etherification agent, reaction conditions and yields of Example 3 and Examples 12-14 are detailed in Table 3.

[0067] Table 3 Different conditions and results of Example 3 and Examples 12-14

[0068] Examples 15 to 17

[0069] Other conditions were the same as those in Example 4, except that the molar ratio of compound 4 to the active amine and the type of active amine were changed. The reaction conditions and yields of Example 4 and Examples 15-17 are detailed in Table 4.

[0070] Table 4 Different conditions and results of Example 4 and Examples 15-17

[0071] Examples 18 to 23

[0072] Other conditions were the same as those in Example 5, except that the molar ratio of compound 5 to L-tartaric acid, reaction temperature, and crystallization temperature were changed. The reaction conditions and results of Example 5 and Examples 18-23 are detailed in Table 5.

[0073] Table 5 Different conditions and results of Example 5 and Examples 18-23

[0074] It should be noted that the above content merely illustrates the technical idea of ​​the present invention and cannot be used to limit the scope of protection of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications all fall within the scope of protection of the claims of the present invention.

Claims

1. A ticagrelor intermediate, characterized in that: The structural formula is shown in Formula 2: Wherein R1 is arbitrarily selected from alkyl acid ions and sulfonate ions.

2. The method for preparing the ticagrelor intermediate according to claim 1, characterized in that: The compound 2 is obtained by reacting the compound 1 with hydrogen and an organic acid in the presence of Raney nickel; wherein K is a substituted or unsubstituted benzyl group.

3. The method for preparing ticagrelor intermediate according to claim 2, characterized in that: The preparation method of compound 2 comprises the following steps: (1) adding compound 1, Raney nickel, molybdenum powder, organic acid and solvent into a reactor and stirring; (2) replacing air in the system with nitrogen; (3) introducing hydrogen and pressurizing; (4) heating to 75-80° C. and reacting; (5) after the reaction is completed, filtering to remove the Raney nickel, and concentrating the filtrate to dryness under reduced pressure to obtain compound 2.

4. The method for preparing a ticagrelor intermediate according to claim 2 or 3, characterized in that: The molar ratio of the compound 1 to the organic acid is 1:1 to 1.

2.

5. The method for preparing ticagrelor intermediate according to claim 2 or 3, characterized in that: The organic acid is selected from any one of acetic acid, p-toluenesulfonic acid or pivalic acid, and it is particularly preferred that the organic acid is pivalic acid.

6. The method for preparing ticagrelor intermediate according to claim 3, characterized in that: The solvent is an alcohol solvent. In a preferred technical solution, the solvent is methanol.

7. A method for preparing a ticagrelor intermediate compound C using the ticagrelor intermediate according to claim 1, characterized in that: After the compound 2 is reacted with an acid anhydride to prepare the compound 3, the intermediate compound C of ticagrelor is further prepared; Wherein, R1 is arbitrarily and independently selected from one of C1-C5 alkyl, H, aryl and substituted aryl; R2 is arbitrarily and independently selected from one of C1-C5 alkyl, aryl and substituted aryl.

8. The method according to claim 7, characterized in that The acid anhydride is one of acetic anhydride, succinic anhydride and phthalic anhydride.

9. The method according to claim 7, characterized in that: The method for further preparing compound 3 to obtain ticagrelor intermediate compound C comprises the following steps: (a) Compound 3 reacts with an etherification agent to form compound 4; (b) Compound 4 reacts with an active amine compound to obtain Compound 5 (Compound C); You can select one or more of the following conditions: (1) The etherifying agent is selected from one of ethylene carbonate, ethylene sulfate and ethylene sulfite; (2) The etherification agent is ethylene carbonate; (3) the molar ratio of compound 3 to the etherification agent is 1:1-2; (4) The reaction temperature of step (a) is 30 to 35° C.; (5) The active amine is dimethylamine or n-butylamine; (6) The molar ratio of compound 4 to the active amine is 1:1-2.

10. The method according to claim 9, characterized in that Compound 5 reacts with tartaric acid to prepare compound 6; You can select one or more of the following conditions: (1) The molar ratio of compound 5 to tartaric acid is 1:1-2; (2) The molar ratio of compound 5 to tartaric acid is 1:1.2; (3) The temperature of the reaction of compound 5 with tartaric acid is 40-55°C; (4) The crystallization temperature of the reaction of compound 5 with tartaric acid is 5-20°C.

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