Ticagrelor intermediates and processes for their preparation

Abstract

The present application relates to ticagrelor intermediates and a preparation method thereof, wherein a halogenated group of compound VI is removed by a deacidifying agent to open a ring, process conditions are simple, and operation is easy; meanwhile, a chiral center in a molecule is constructed by using a transaminase to prepare compound VII from compound VI, conditions are more mild, chiral selectivity is better, raw material utilization is improved, chiral separation or chiral reduction process is avoided, and industrialized production is more beneficial. The disclosed technical scheme can be connected with a process for preparing compound VII from D-ribose as a starting material, forming a process for preparing target compound ticagrelor intermediate compound VII from compound I (D-ribose) as a raw material, synthesizing compound II by reacting with methanol, then synthesizing compound III by sulfonylization of compound II, then synthesizing compound IV by halogen substitution of compound III, and further opening a ring, closing a ring, and catalyzing by a transaminase.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to the field of drug synthesis, more particularly to a ticagrelor intermediate and a preparation method thereof. BACKGROUND

[0002] Ticagrelor is an oral selective P2Y12 receptor inhibitor, which can prevent ADP-mediated platelet activation and aggregation, reduce the probability of cardiovascular disease death, and the rate of acute coronary syndrome (ACS) or myocardial infarction (MI) in patients with myocardial infarction and stroke. The structural formula is as follows:

[0003]

[0004] Compound VII is an important intermediate compound in the synthesis of ticagrelor, and the structural formula is as follows:

[0005]

[0006] A preparation method is reported in the document Journal of the Chemical Society, Perkin Transactions 1, 1994 (6): 613-614, and the main steps are as follows:

[0007]

[0008] A new preparation method of a ticagrelor intermediate is also disclosed in CN102659815B, and the specific reaction route of the method is as follows:

[0009]

[0010] A preparation method of a ticagrelor intermediate is disclosed in CN104114542A, and the specific reaction route of the method is as follows:

[0011]

[0012] WO2010069408, WO2012063126, etc. disclose a preparation process of intermediate compound VII, and the specific reaction route is as follows:

[0013]

[0014] It is evident that this intermediate compound, as an important intermediate, is a hot topic and a challenging issue for researchers in this field. However, all three preparation processes mentioned above have their own shortcomings. For example, in the first process, the use of palladium on carbon as a catalyst results in high costs and difficulty in controlling the chirality of the product; it also requires zinc powder for ring-opening catalysis, leading to complex post-processing and the need to consider zinc powder recovery. In the second process, the debenzylation step to obtain the chiral compound X has a long reaction time and low yield, making it unsuitable for industrial production. The third process also requires palladium on carbon as a catalyst, resulting in high costs and difficulty in controlling the chirality of the product. Furthermore, subsequent reactions require separate protection of the hydroxyl and amino groups before selective reactions, effectively increasing the number of reaction steps and workload. In the fourth reaction, the target compound is synthesized through a series of reactions including amination, oxidation, acidolysis, ketalization, reduction, amino protection, esterification, reduction, and deprotection. This method suffers from a long route and low yield. Summary of the Invention

[0015] The technical problem to be solved by this invention is to provide a new preparation method for the important ticagrelor intermediate compound VII, which simplifies the process, reduces costs, and improves reaction yield and purity.

[0016] To solve the above-mentioned technical problems, the present invention discloses a method for preparing ticagrelor intermediate compound VII, specifically, compound VI reacts with an amino donor in the presence of coenzyme PLP and under the catalysis of transaminase to obtain compound VII;

[0017]

[0018] More preferably, the amino donor is isopropylamine or alanine.

[0019] More preferably, the mass ratio of compound VI to transaminase is 1:1 to 10.

[0020] More preferably, the mass ratio of compound VI to the amino donor is 1:0.1 to 10.

[0021] More preferably, the mass ratio of compound VI to coenzyme PLP is 1:0.001 to 1.

[0022] Furthermore, this invention also discloses an intermediate compound for synthesizing ticagrelor intermediate compound VII, the structural formula of which is as follows:

[0023]

[0024] Furthermore, the preparation method of compound VI was disclosed, which involves cyclizing compound V under alkaline conditions to synthesize compound VI.

[0025] More preferably, the alkali can be one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, and sodium methoxide, with sodium methoxide being the most preferred.

[0026] More preferably, the molar ratio of compound V to the base is 1:1 to 2, more preferably 1:1.2.

[0027] In addition, this invention also discloses another intermediate compound for the synthesis of ticagrelor intermediate compound VII, the structural formula of which is as follows:

[0028]

[0029] Furthermore, it is disclosed that compound V is formed by ring-opening of compound IV by removing a halogenated group under the action of a deacidifying agent, and its synthetic route is as follows:

[0030]

[0031] More preferably, the molar ratio of compound IV to the deacidifying agent is 1:1 to 2, more preferably 1:1.5.

[0032] Furthermore, in this invention, the deacidifying agent is preferably one of DBU, pyridine, triethylamine, and diisopropylethylamine, with DBU being the most preferred.

[0033] By adopting the technical solution disclosed in this invention, a new method for preparing the target compound VII can be provided. This method involves ring-opening by removing a halogenated group from compound VI under the action of a deacidifier. The process conditions are simple and the operation is easy. Simultaneously, the chiral center in the molecule is constructed using transaminase catalysis, and compound VII is prepared from compound VI. The conditions are milder, the chiral selectivity is better, the raw material utilization rate is improved, and the chiral resolution or reduction process is avoided, making it more conducive to industrial production. Furthermore, the technical solution disclosed in this invention can be linked with the process for preparing compound VII from D-ribose as a starting material, forming a process where compound I (D-ribose) is used as a starting material to synthesize compound II through reaction with methanol. Then, compound II is sulfonated under alkaline conditions to synthesize compound III. Next, compound III undergoes halogen substitution to synthesize compound IV, and further ring-opening, ring-closing, and transaminase catalysis are used to obtain the intermediate compound ticagrelor, compound VII. The process route is as follows:

[0034] Detailed Implementation

[0035] To better understand the present invention, we will further elaborate on the present invention below with reference to specific embodiments.

[0036] Example 1: Synthesis of Compound II

[0037]

[0038] Compound I (40 g, 0.267 mol) was added to a dried reactor, along with methanol (120 ml) and acetone (120 ml), and stirred until homogeneous. The temperature was maintained at 30°C. Then, thionyl chloride (6.3 g, 0.053 mol) was added, and the reaction was carried out over 15 minutes until the solution became completely clear. The temperature was then maintained at 30°C, and the reaction was stirred for 18-20 hours.

[0039] After the reaction was complete, triethylamine (10.8 g, 0.107 mol) was added dropwise to adjust the concentration to approximately 8. The solvent was then evaporated under reduced pressure at 60°C and concentrated to an oily state. The mixture was cooled to room temperature, the stirring was stopped, and DCM (120 ml) was added to dilute the material. Water (60 ml) was then added, and the mixture was stirred for 15 minutes. The mixture was allowed to stand and separate into layers. The aqueous layer was extracted twice more with DCM (30 ml), and the organic layers were combined to form a DCM solution of compound II.

[0040] Example 2 Synthesis of Compound III

[0041]

[0042] Add p-toluenesulfonyl chloride (66g, 0.346mol) and triethylamine (56g, 0.553mol) to the reactor. Cool the reactor to 0-5℃ and add compound II / DCM solution dropwise in batches while controlling the temperature. After the addition is complete, keep the temperature for 1 hour. Then raise the temperature to 20-25℃ and stir the reaction for 4-5 hours.

[0043] After the reaction was complete, the mixture was washed twice with 1400 L of water, allowed to stand to separate the organic layer, and then distilled under reduced pressure using DCM. After evaporation to dryness, anhydrous ethanol (160 ml) was added and the mixture was stirred to induce crystallization overnight. The mixture was then centrifuged. The material was placed in a double-cone oven at 45-50 °C to obtain dry crystals of compound III (71.62 g, 0.2 mol), with an overall yield of 74.9% for both steps.

[0044] Example 3 Synthesis of Compound IV

[0045]

[0046] Compound III (71.62 g, 0.2 mol) and sodium chloride (17.5 g, 0.3 mol) were added to a dry reactor. 2-Butanone (300 ml) was added under nitrogen protection. The mixture was stirred until homogeneous and heated to reflux (T = 81-83 °C). The mixture was kept at this temperature and stirred for 20-24 h.

[0047] After the reaction was complete, the internal temperature was adjusted to below 80℃, 2-butanone was distilled off, water (150 ml) was added, and toluene (180 ml) was pumped in. The mixture was stirred until the solution was completely clear, allowed to stand and separate into layers, the organic layer was removed, and the aqueous layer was extracted with toluene (30 ml) to obtain the extract. The organic layer and the extract were combined and washed once with water (30 ml). Toluene was evaporated off, and the residue was compound IV (43.96 g, 0.197 mol), with a yield of 98.5%.

[0048] Example 4 Synthesis of Compound V

[0049]

[0050] Compound IV (33.4 g, 0.15 mol) and methanol (100 ml) were added to the reactor and stirred until completely dissolved. DBU (34.3 g, 0.22 mol) was then added, and the system was heated to 30-40 °C and stirred for 5-6 h. After the reaction was complete, methanol was distilled off, water (150 ml) was added, and toluene (180 ml) was added. The mixture was stirred until the solution was completely clear, allowed to stand and separate into layers. The organic layer was collected, and the aqueous layer was extracted with toluene (30 ml) to obtain the extract. The organic layer and the extract were combined and washed once with water (30 ml). Toluene was evaporated off, and the residue was compound V (20.97 g, 0.122 mol), with a yield of 81.2%.

[0051] Example 5: Synthesis of Compound VI

[0052]

[0053] Compound V (20.66 g, 0.12 mol) and THF (100 ml) were added to the reactor, the temperature was lowered to 0 °C, sodium methoxide (7.78 g, 0.144 mol) was added, and the mixture was stirred until completely dissolved. The system was then heated to room temperature and stirred for 1–2 h.

[0054] After the reaction was complete, saturated ammonium chloride solution (50 ml) was added to the system, stirred, allowed to stand, and separated into layers. The organic layer was taken, and THF was evaporated to dryness. The residue was compound VI (19.42 g, 0.113 mol), with a yield of 94%.

[0055] Example 6 Synthesis of Compound VII

[0056] Construction of T-002 expression strain

[0057] After synthesizing the transaminase gene, the expression vector pET-28a(+) was selected. The exogenous gene was inserted through the EcoRI and HindIII double restriction sites. The constructed vector was then inserted into E. coli BL21(DE3). Positive clones were screened by plating on Kna resistance plates, and plasmids were extracted and sequenced for verification. Finally, the recombinant engineered bacteria containing the esterase gene were confirmed.

[0058] Recombinant bacteria fermentation to produce enzymes for the preparation of compound VII

[0059] (1) Preparation of crude transaminase solution: The recombinant bacteria were inoculated into 10 mL of LB medium and cultured overnight at 37°C with shaking. The inoculation was transferred to LB medium at a rate of 1% and cultured at 37°C until OD600 = 0.6-0.8. IPTG was added to a final concentration of 0.5 mM and induced at 20°C for 16 h. The wet cells were collected by centrifugation, washed twice, and then sonicated to obtain diluted crude enzyme solution.

[0060] (2) Enzyme-catalyzed preparation of compound VII

[0061]

[0062] 0.2 M pH 7.0 PB buffer (9 mL), isopropylamine (0.1 g), 10 mL diluted crude enzyme solution (containing approximately 1 g of wet cells), PLP (0.001 g), compound VI (1 g, 5.8 mmol), and DMSO (4 mL) were added to the reactor. The reaction was carried out overnight at 40 °C and 220 rpm using a shaker. After the reactants had reacted completely, an equal volume of ethyl acetate was added for extraction twice. The upper ethyl acetate phase was collected, evaporated to dryness, and compound VII solid (0.934 g, 5.39 mmol) was obtained, with a yield of 92.7%. The evaporated organic solvent was recovered.

[0063] Examples 7-11

[0064] Other conditions are the same as in Example 4, except that the molar ratio of compound IV to the deacidifying agent and the type of deacidifying agent are changed. The reaction conditions and yields of Examples 4 and 7-11 are detailed in Table 1.

[0065] Table 1: Different conditions and results of Examples 4 and 7-11

[0066]

[0067] Examples 12-15

[0068] Other conditions are the same as in Example 5, except that the molar ratio of compound V to the base and the type of base are changed. The reaction conditions and results of Examples 5 and 12-15 are detailed in Table 2.

[0069] Table 2. Different conditions and results for Examples 5 and 12-15

[0070]

[0071]

[0072] Example 16

[0073] Other conditions are the same as in Example 6, except that the mass ratio of compound VI to transaminase, the mass ratio of transaminase to coenzyme PLP, and the mass ratio of compound VI to amino donor are changed. The reaction conditions and results of Examples 6 and 16 are detailed in Table 3.

[0074] Table 3. Different conditions and results of Examples 6 and 16

[0075]

[0076] The above describes specific embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A method for preparing ticagrelor intermediate compound VII, characterized in that: Compound V is formed by removing the halogenated group X from compound IV under the action of a deacidifying agent to open the ring. Compound VI is synthesized by closing the ring of compound V under the action of an alkaline agent. Compound VI reacts with an amino donor in the presence of coenzyme PLP and under the catalysis of transaminase to obtain compound VII. ； The mass ratio of compound VI to transaminase is 1:1~10.

2. The method for preparing ticagrelor intermediate compound VII according to claim 1, characterized in that: The amino donor is isopropylamine or alanine.

3. The method for preparing ticagrelor intermediate compound VII according to claim 2, characterized in that: The mass ratio of compound VI to the amino donor is 1:0.1~10.

4. The method for preparing ticagrelor intermediate compound VII according to claim 1, characterized in that: The mass ratio of compound VI to coenzyme PLP is 1:0.001~1.

5. The method for preparing ticagrelor intermediate compound VII according to claim 1, characterized in that: The deacidifying agent is one of DBU, pyridine, triethylamine, and diisopropylethylamine.

6. The method for preparing ticagrelor intermediate compound VII according to claim 1, characterized in that: The deacidifying agent is DBU.

7. The method for preparing ticagrelor intermediate compound VII according to claim 1, characterized in that: The molar ratio of compound IV to the deacidifying agent is 1:1~2.

8. The method for preparing ticagrelor intermediate compound VII according to claim 7, characterized in that: The molar ratio of compound IV to the deacidifying agent is 1:1.

5.

9. A method for preparing ticagrelor intermediate compound VII from D-ribose as a starting material, characterized in that, Using compound I as a starting material, compound II was synthesized by reacting it with methanol. Then, compound II was sulfonated with R1Cl under alkaline conditions to synthesize compound III. Next, compound III was substituted with halogen X to synthesize compound IV. Further ring-opening, ring-closing, and transaminase catalysis were performed to obtain the intermediate compound VII, which is the target compound ticagrelor. The specific process route is as follows: ； R1Cl is sulfonyl chloride, and halogen X is Cl.

10. The method for preparing ticagrelor intermediate compound VII from D-ribose as a starting material according to claim 9, characterized in that: The molar ratio of compound V to sodium methoxide is 1:1~2.

11. The method for preparing ticagrelor intermediate compound VII from D-ribose as a starting material according to claim 10, characterized in that: The molar ratio of compound V to sodium methoxide is 1:1.2.

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