Process for the preparation of a ticagrelor intermediate

Abstract

The application relates to the technical field of drug intermediate synthesis, in particular to a preparation method of a ticagrelor intermediate, and the synthesis route is as follows: wherein R is linear or branched C1-C6 alkyl, cycloalkyl or aralkyl which can be unsubstituted, monosubstituted or polysubstituted; and X is Cl or Br. The method specifically comprises the following steps: 1) synthesizing compound 1 by the docking of halogenated acetamide and phosphite; 2) synthesizing compound 3 by the docking of Wittig reaction of the prepared compound 1 and compound 2; and 3) obtaining the target compound 4 by the Hofmann degradation of the prepared compound 3 and the salt formation with mandelic acid. The preparation method shortens the process steps, the process is simpler, and the overall yield of the process is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for preparing ticagrelor intermediate. Background Technology

[0002] Ticagrelor is an oral selective P2Y12 receptor inhibitor that prevents ADP-mediated platelet activation and aggregation, reducing the probability of death from cardiovascular disease and the historical rate of acute coronary syndrome (ACS) or myocardial infarction (MI) in patients with myocardial infarction and stroke.

[0003] It is an important intermediate used in the preparation of ticagrelor. A synthetic method for preparing this intermediate is reported in the literature *Organic Process Research & Development*, 2002, 6(5): 618-620. The main steps are as follows:

[0004]

[0005] This process uses ethyl diethylphosphonoacetate as the witting reagent. After cyclization, the product undergoes amide conversion via ammonia, followed by Hoffmann degradation to obtain the target product. However, the ammonia conversion step in this method requires excess ammonia, resulting in a large amount of residual ammonia. This necessitates the addition of a recovery unit to meet production needs, increasing equipment costs and making the production process relatively difficult.

[0006] CN115850086A discloses a method for preparing ticagrelor intermediates. This method involves cyclizing compound III to form compound IV under alkaline conditions, then synthesizing compound V under the catalysis of transaminase. Subsequently, compound V is salted with D-mandelic acid to form ticagrelor intermediate compound VI. The synthetic route is as follows:

[0007]

[0008] However, this preparation method requires the construction of expression strains and the production of compound V through fermentation of recombinant bacteria, which makes the production process relatively complex. Summary of the Invention

[0009] To address the aforementioned problems in the prior art, the present invention aims to provide a method for preparing ticagrelor intermediates.

[0010] To achieve the above objectives, the present invention provides the following technical solution:

[0011] A method for preparing a ticagrelor intermediate, the synthetic route of which is as follows:

[0012]

[0013] Wherein, R is a straight-chain or branched C1-C6 alkyl or cycloalkyl group, or R is an aralkyl group, which may be unsubstituted, monosubstituted or polysubstituted; X is Cl or Br.

[0014] Specifically, the following steps are included:

[0015] (1) Compound 1 was synthesized by docking haloacetamide with phosphite;

[0016] (2) Compound 1 and compound 2 were synthesized by Wittig reaction;

[0017] (3) The obtained compound 3 underwent Hofmann degradation and formed a salt with mandelic acid to obtain the target compound 4;

[0018] Furthermore, in step (1), no additional reaction solvent is added, and the reaction temperature is 140–160 °C.

[0019] Furthermore, in step (1), the molar ratio of haloacetamide to phosphite is 1:1.3-2.

[0020] Furthermore, in step (2), the reaction solvent is toluene, and the reaction temperature is 70-80℃.

[0021] Furthermore, in step (2), the molar ratio of compound 2 to compound 1 is 1:1 to 1.5.

[0022] Furthermore, in step (3), compound 3 undergoes Hofmann degradation in the presence of hypochlorite, wherein the hypochlorite is any one of sodium hypochlorite, potassium hypochlorite, and calcium hypochlorite.

[0023] Furthermore, in step (3), the molar ratio of compound 3, hypochlorite, and mandelic acid is 1:1 to 1.5:1 to 1.2.

[0024] Compared with the prior art, the beneficial effects of the present invention are:

[0025] This invention prepares compound 3 by directly reacting a self-made amide phosphine ylide reagent with compound 2. Compared with the prior art, this method shortens the process steps, simplifies the process, and improves the overall yield. Attached Figure Description

[0026] Figure 1 The 1H NMR spectrum of compound 1 prepared in Example 1 is shown. Detailed Implementation

[0027] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1

[0029]

[0030] 2-Chloroethylamide (9.35 g, 0.1 mol) and triethyl phosphite (24.92 g, 0.15 mol) were added to a dry reactor, stirred and mixed, and the air was replaced with nitrogen three times. The temperature was raised to 140-160 °C and the reaction was maintained at this temperature with stirring for 5 h. The system changed from turbid to yellow-green.

[0031] After the reaction was complete, the mixture was allowed to cool naturally, resulting in the precipitation of a solid. After crystallization for 1 hour, the mixture was filtered, and the filter cake was dried to obtain compound 1 (16.55 g, 0.0848 mol), with a yield of 84.8%. The 1H NMR spectrum of compound 1 is shown below. Figure 1 As shown.

[0032] Example 2

[0033]

[0034] Compound 1 (21.47 g, 0.11 mol) was added to a dry reactor, along with potassium tert-butoxide (11.22 g, 0.1 mol) and toluene (150 mL). The air was purged with nitrogen three times, and the temperature was raised to 25–30 °C. A toluene solution (100 mL) containing compound 2 (15.61 g, 0.1 mol) was added dropwise. After the addition was complete, the temperature was further raised to 70–80 °C, and the reaction was allowed to proceed for 16 h.

[0035] After the reaction was complete, the mixture was allowed to cool naturally. The system was washed twice with water, and the organic layer was depressurized to recover the dry solvent, yielding compound 3 (16.23 g, 0.0823 mol), with a yield of 82.3%.

[0036] Example 3

[0037]

[0038] Add sodium hydroxide (2g, 0.05mol) to the reactor, add water (200mL) and stir to dissolve. Then add compound 3 (19.72g, 0.1mol), stir and cool to 0-10℃. Add 10% sodium hypochlorite solution (81.9g, 0.11mol) dropwise to the system, completing the addition in about 1 hour. Raise the temperature to about 55-65℃ and react for 16 hours.

[0039] After the reaction was complete, the mixture was allowed to cool naturally. Toluene (150 mL) was added to the system, and the organic layer was separated after stirring and extraction. The dry toluene was recovered under reduced pressure. Methanol (100 mL) was added to the residue, and the mixture was heated to 55-65 °C and stirred to dissolve. A methanol solution (100 mL) containing D-mandelic acid (16.74 g, 0.11 mol) was added dropwise to the ethanol solution. After the addition was complete, the mixture was stirred and reacted for 1 h.

[0040] The mixture was allowed to cool naturally to room temperature, and a solid precipitated out. The mixture was filtered, and the filter cake was dissolved in methanol (100 mL) by heating. The temperature was then lowered to 0–5 °C, and the mixture was purified by crystallization for 2 hours. The mixture was filtered again, and the second filter cake was dried to obtain compound 4 (27.57 g, 0.0858 mol), with a yield of 85.8%.

[0041] Examples 4-7

[0042] Other conditions are the same as in Example 1, except that the molar ratio of haloacetamide to phosphite, the type of X group, and the type of R group are changed. The reaction conditions and yields of Examples 1 and 4-7 are detailed in Table 1.

[0043] Table 1. Different conditions and results for Examples 1 and 4-7

[0044] 1 1:1.5 Cl Ethyl 84.8 4 1:1.3 Cl Ethyl 83.5 5 1:2 Cl Ethyl 84.3 6 1:1.5 Br Ethyl 84.3 7 1:1.5 Cl propyl 83.2

[0045] Examples 8-9

[0046] Other conditions are the same as in Example 2, except that the molar ratio of compound 2 to compound 1 is changed. The reaction conditions and yields of Examples 2 and 8-9 are detailed in Table 2.

[0047] Table 2. Different conditions and results of Examples 2 and 8-9

[0048]

[0049] Examples 10-13

[0050] Other conditions are the same as in Example 3, except that the molar ratio of compound 3, hypochlorite, and mandelic acid, and the type of hypochlorite are changed. The reaction conditions and yields of Examples 3 and 10-13 are detailed in Table 3.

[0051] Table 3. Different conditions and results of Examples 3 and 10-13

[0052] 3 1:1.1:1.1 Sodium hypochlorite 85.8 10 1:1:1 Sodium hypochlorite 83.1 11 1:1.5:1.2 Sodium hypochlorite 85.5 12 1:1.1:1.1 Potassium hypochlorite 85.6 13 1:1.1:1.1 Calcium hypochlorite 82.4

[0053] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a ticagrelor intermediate, characterized in that, Includes the following steps: (1) Compound 1 was synthesized by docking haloacetamide with phosphite; no additional reaction solvent was added, the reaction temperature was 140~160℃, and the molar ratio of haloacetamide to phosphite was 1:1.3~2; ； (2) Compound 1 and compound 2 were synthesized by Wittig reaction; the reaction solvent was toluene, the reaction temperature was 70~80℃, and the molar ratio of compound 2 to compound 1 was 1:1~1.

5. ； (3) The obtained compound 3 undergoes Hofmann degradation in the presence of hypochlorite and forms a salt with mandelic acid to obtain target compound 4; the hypochlorite is any one of sodium hypochlorite, potassium hypochlorite and calcium hypochlorite; the molar ratio of compound 3, hypochlorite and mandelic acid is 1:(1~1.5):(1~1.2). ； Wherein, R is a straight-chain or branched C1-C6 alkyl group; X is Cl or Br.

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