Synthesis method of key intermediate of ticagrelor

Abstract

The invention belongs to the field of organic chemistry, and particularly relates to a synthesis method of a ticagrelor key intermediate, which comprises the following steps: (1) taking an intermediate A as a raw material, and removing a hydroxyl protecting group under an acidic condition to obtain a compound with a structural formula B, and (2) taking the compound with the structural formula B as a raw material, and reacting under an acidic condition to obtain the ticagrelor key intermediate. And (3) taking the compound of the structural formula C as a raw material, and obtaining the ticagrelor key intermediate of a structural formula V under an alkaline condition. The method for preparing the ticagrelor key intermediate is green and safe, mild in reaction condition, low in cost and high in yield, the prepared intermediate B aqueous solution is directly used for the next-step continuous flow reaction through a one-pot method, generation of polymerization impurities of an intermediate C can be well controlled, the production cost is reduced, and the method is more environmentally friendly and efficient.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemistry, and particularly relates to a synthesis method of a key intermediate of Ticagrelor. BACKGROUND

[0002] Ticagrelor (cas No. 274693-27-5), chemical name is (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3, 4-difluorophenyl)cyclopropyl]amino]-5-propylthiotriazolo[4, 5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1, 2-cyclopentanediol, and the trade name is Ticagrelor.

[0003] The molecular structure of Ticagrelor is as follows:

[0004]

[0005] The polymerization impurity of the intermediate C of Ticagrelor is as follows:

[0006]

[0007] Ticagrelor is a P2Y12 platelet inhibitor, which is mainly used in perioperative period and postoperative period for adult patients with acute coronary syndrome (such as unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), including patients who have received drug treatment, percutaneous coronary intervention (PCI) treatment and coronary artery bypass grafting (CABG).

[0008] For the synthesis of Ticagrelor, the key intermediate V is currently a hotspot of process research. The second step of diazotization reaction will produce the polymerization impurity of the intermediate C, which will decompose and condense into the impurity B in the EP pharmacopoeia in the subsequent reaction process. The above key intermediate is prepared by the following route:

[0009]

[0010] In the patent US6525060B1, the intermediate A is used as raw material, iron powder / acetic acid reduction, nitrosoisopentyl ester cyclization, ammoniation to obtain 8-azane adenine derivative compound I-5, then reacted with 2-trifluoromethylsulfonyloxy acetic acid methyl ester under the action of butyl lithium, then bromination, nucleophilic reaction with difluorophenyl cyclopropylamine under the action of DIPEA, DIBAI-H reduction of ester group, and finally hydrolysis and deprotection in trifluoroacetic acid to obtain the key intermediate V.

[0011]

[0012] WO2011017108A2 also uses a similar synthetic route, the difference is that the nucleophilic reaction is carried out under basic triethylamine conditions first, and then the nitro group is reduced to amino group by iron powder, and then the intermediate C is obtained by ring closure under the action of appropriate alkali metal sodium nitrite salt, and then condensed with difluorophenyl cyclopropylamine to obtain the intermediate V by deprotection.

[0013]

[0014] In the above patents, the nitro group is first reduced, then the nucleophilic reaction, diazonium salt ring closure, condensation with difluorophenyl cyclopropylamine, and finally deprotection to obtain the crude ticagrelor. The reaction is complicated, the total yield is low, and the impurities are more, and the production cost is high.

[0015] In summary, it is urgent to develop a new method for preparing the key intermediate V of ticagrelor with low cost, mild reaction conditions and more environmentally friendly. SUMMARY

[0016] In order to overcome the shortcomings of the prior art, the present application provides a method for preparing a key intermediate of ticagrelor with green and safe reaction, mild reaction conditions, low cost and high yield. The aqueous solution of the prepared intermediate B is directly used for the next continuous flow reaction by one-pot method, which can well control the generation of polymerization impurities of intermediate C, reduce the production cost, and is more environmentally friendly and efficient.

[0017] In order to achieve the above purpose, the technical scheme of the present application is:

[0018] A synthesis method of a ticagrelor intermediate with the structure formula V, comprising the following steps:

[0019] Step 1: using intermediate A as raw material, dehydroxyl protecting group under concentrated sulfuric acid to obtain intermediate B;

[0020] Step 2: using intermediate B as raw material, reacting with sodium nitrite under acidic conditions to obtain intermediate C;

[0021] Step 3: using intermediate C as raw material, under alkaline conditions, the key intermediate of ticagrelor with structure formula V is obtained; the reaction formula is as follows:

[0022]

[0023] Preferably, the reaction solvent of step 1 is methanol aqueous solution.

[0024] Preferably, the molar ratio of the acid in step 1 to the reaction feeding amount of intermediate A is 1:1 to 20:1; more preferably 2:1 to 5:1.

[0025] Preferably, the acid used in step 1 is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and p-toluenesulfonic acid; more preferably, sulfuric acid.

[0026] Preferably, the reaction temperature in step 1 is 0-80℃, more preferably 40-60℃.

[0027] Preferably, the reaction solvent in step 2 is selected from ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, DMSO, and toluene, with ethyl acetate being more preferred.

[0028] Preferably, the acid required for the reaction in step 2 is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, and p-toluenesulfonic acid; more preferably, sulfuric acid.

[0029] Preferably, the molar ratio of the acid, sodium nitrite, and intermediate A used in step 2 is 0.5:0.8:1 to 4:2:1; more preferably 1.3:1.2:1.

[0030] Preferably, the reaction temperature in step 2 is -10 to 20°C, more preferably 15°C.

[0031] Preferably, the concentrations of reaction intermediate B and sodium nitrite aqueous solution in step 2 are 5%-70% and 10%-80%, respectively; more preferably, the concentration of intermediate B aqueous solution is 30% and sodium nitrite aqueous solution is 40%.

[0032] Preferably, the volume (ml) of the reaction solvent in step 2 is 2-20 times the mass of structural formula B, more preferably 8 times.

[0033] Preferably, in step 2, the flow rate of the aqueous solution of reaction intermediate B is 1-20 ml / min, the flow rate of the sodium nitrite aqueous solution is 0.2-2 ml / min, the flow rate of the solvent is 2-20 ml / min, and the reaction residence time is 3-30 minutes. More preferably, the flow rate of the aqueous solution of intermediate B is 6 ml / min, the flow rate of the sodium nitrite aqueous solution is 0.94 ml / min, the flow rate of the solvent is 8 ml / min, and the reaction residence time is 10 minutes.

[0034] Preferably, the molar ratio of difluorophenylcyclopropylamine mandelate used in step 3 to intermediate A is 0.7:1 to 2:1, more preferably 1:1.

[0035] Preferably, the reaction temperature in step 3 is 10-60℃, more preferably 20-30℃.

[0036] Compared with existing processes, this invention has the following advantages: the aqueous solution of intermediate B generated in step 1 is directly used in the reaction in step 2. The continuous flow microchannel reaction in step 2 can effectively control the generation of polymerization impurities in intermediate C, so that the total yield from intermediate A to intermediate V reaches more than 92%. The reaction conditions are mild, avoiding the use of batch reaction in diazotization, making it more green and safe. At the same time, it can effectively control the generation of dimerization impurities, providing a better means of controlling the quality of API. Attached Figure Description

[0037] Figure 1 This is the HPLC spectrum of compound V from Example 1.

[0038] Figure 2 This is the H-NMR spectrum of compound V from Example 1. Detailed Implementation

[0039] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0040] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products.

[0041] Example 1

[0042] 182g of drinking water, 24g of concentrated sulfuric acid and 125g of methanol were added to a 500ml reaction flask, followed by 79g (0.19mol) of ticagrelor intermediate A. The mixture was heated to 45℃ and reacted for 1 hour. The reaction was then carried out under reduced pressure for 2 hours. The mixture was spotted by TLC. After the reaction was completed, 40g of drinking water was added to obtain 260g of 27% aqueous solution of intermediate B, which was used directly in the next step of the reaction. The aqueous solution of intermediate B prepared above, 356 g of ethyl acetate, and 41.6 g (0.23 mol) of sodium nitrite aqueous solution were pumped into a mixer at flow rates of 11.9 ml / min, 16.3 ml / min, and 1.9 ml / min, respectively. After thorough mixing, the mixture was introduced into a microchannel reactor for reaction. The reaction residence time was 5 min, and the reaction temperature was controlled at 10 °C. The reaction solution was then discharged and spotted by TLC. After the reaction was completed, the mixture was allowed to stand and separate into layers. The aqueous phase was extracted once with 214 g of ethyl acetate. The combined organic phases were washed once with 222 g (0.13 mol) of sodium bicarbonate aqueous solution to obtain an ethyl acetate solution of intermediate C. 57.56 g (0.18 mol) of difluorophenylcyclopropylamine mandelate and 483 g (0.42 mol) of sodium carbonate aqueous solution were added directly to the reaction flask containing the ethyl acetate solution of intermediate C. The temperature was controlled at 35 °C, and the reaction was carried out for 4 hours. The reaction was then spotted by TLC until the end of the reaction. The mixture was allowed to stand and separate into layers. The ethyl acetate solution of the crude product was recovered. The crude product was crystallized with an aqueous methanol solution to obtain the key intermediate of ticagrelor with structural formula V (92.6 g, total yield 94%, polymerization impurities in intermediate C were not detected, HPLC: 99.8%).

[0043] Example 2

[0044] 546g of drinking water, 72g of concentrated sulfuric acid, and 200g of methanol were added to a 1L reaction flask, followed by 237g (0.57mol) of ticagrelor intermediate A. The mixture was heated to 50℃ and reacted for 1 hour. The reaction was then carried out under reduced pressure for 2 hours. The mixture was spotted by TLC. After the reaction was completed, 120g of drinking water was added to obtain 785g of 27% aqueous solution of intermediate B, which was used directly in the next step of the reaction. The aqueous solution of intermediate B prepared above, 1100g of ethyl acetate, and 125g (0.7mol) of sodium nitrite aqueous solution were pumped into a mixer at flow rates of 3ml / min, 4ml / min, and 0.7ml / min, respectively. After thorough mixing, the mixture was introduced into a microchannel reactor for reaction. The reaction residence time was 20min, and the reaction temperature was controlled at 15℃. The reaction solution was then discharged and spotted by TLC. After the reaction was completed, the mixture was allowed to stand and separate into layers. The aqueous phase was extracted once with 660g of ethyl acetate. The combined organic phases were washed once with 666g (0.39mol) of sodium bicarbonate aqueous solution to obtain an ethyl acetate solution of intermediate C. 173g (0.54mol) of difluorophenylcyclopropylamine mandelate and 1500g (1.26mol) of sodium carbonate aqueous solution were directly added to the reaction flask containing the ethyl acetate solution of intermediate C. The temperature was controlled at 40℃, and the reaction was carried out for 4 hours. The reaction was spotted by TLC until the end of the reaction. The mixture was allowed to stand and separate into layers. The ethyl acetate solution of the crude product was recovered. The crude product was crystallized with an aqueous methanol solution to obtain the key intermediate of ticagrelor with structural formula V (274 g, total yield 92.7%, polymerization impurities in intermediate C were not detected, HPLC: 99.8%).

[0045] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for synthesizing a ticagrelor intermediate with structural formula V, comprising the following steps: Step 1: Using intermediate A as a raw material, dehydroxyl protecting groups are removed under acidic conditions to obtain intermediate B; Step 2: Using intermediate B as a raw material, react with sodium nitrite under acidic conditions to obtain intermediate C; Step 3: Using intermediate C as a starting material, under alkaline conditions, the key intermediate of ticagrelor with structural formula V is obtained; the reaction formula is as follows:

2. The synthesis method according to claim 1, characterized in that, The reaction solvent in step 1 is an aqueous methanol solution; the molar ratio of the acid and intermediate A in step 1 is 1:1 to 20:1; the acid used in step 1 is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and p-toluenesulfonic acid; the reaction temperature in step 1 is 0-80℃, and the aqueous solution of intermediate B obtained by vacuum distillation is directly used in the next step of the reaction.

3. The synthesis method according to claim 2, characterized in that, The reaction solvent in step 2 is selected from ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, DMSO and toluene; sodium nitrite is in the form of an aqueous solution; the molar ratio of acid, sodium nitrite and intermediate A used in step 2 is 0.5:0.8:1 to 4:2:1; the reaction temperature in step 2 is -10℃ to 20℃.

4. The synthesis method according to claim 3, characterized in that, In step 2, the aqueous solution of reaction intermediate B, the aqueous solution of sodium nitrite, and the reaction solvent are pumped into the mixer simultaneously. After being fully mixed, they enter the microchannel reactor for reaction. The reaction solution is then processed to obtain the reaction solvent solution of intermediate C.

5. The synthesis method according to claim 4, characterized in that, In step 2, the concentrations of reaction intermediate B and sodium nitrite aqueous solution are 5%-70% and 10%-80%, respectively, and the volume of solvent is 2-20 times that of intermediate B.

6. The synthesis method according to claim 4, characterized in that, In step 2, the flow rate of the aqueous solution of reaction intermediate B is 1-20 ml / min, the flow rate of the sodium nitrite aqueous solution is 0.2-2 ml / min, the flow rate of the solvent is 2-20 ml / min, and the reaction residence time is 3-30 minutes.

7. The synthesis method according to claim 1, characterized in that, In step 3, the material is fed in the form of solution of structure C from the previous step. The molar ratio of difluorophenylcyclopropylamine mandelate used in step 3 to intermediate A is 0.7:1 to 2:

1. The reaction temperature in step 3 is 10-60℃.

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