CN112778263A

CN112778263A - Ticagrelor and intermediate impurity thereof, and preparation method thereof

Info

Publication number: CN112778263A
Application number: CN202011642437.7A
Authority: CN
Inventors: 李海峰; 王子坤; 朱晓峰
Original assignee: Pharmaresources Shanghai Co ltd
Current assignee: Pharmaresources Shanghai Co ltd
Priority date: 2020-12-31
Filing date: 2020-12-31
Publication date: 2021-05-11

Abstract

The invention discloses a ticagrelor impurity and a preparation method thereof, wherein the structure of the ticagrelor impurity corresponds to the structural formula of an API dimer:

the preparation method comprises the steps of using TKG dimer to obtain a crude product after TKMD substitution, cyclization and TKB substitution and deprotection, and then separating to obtain an impurity solution with the purity of more than or equal to 99.0%. Meanwhile, the invention also provides a ticagrelor intermediate impurity and a preparation method thereof. The structure confirmation and pure product preparation of the ticagrelor impurity can be used for qualitative and quantitative analysis of the ticagrelor process impurity, and have an important effect on the quality control of ticagrelor.

Description

Ticagrelor and intermediate impurity thereof, and preparation method thereof

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to ticagrelor and intermediate impurities thereof and a preparation method.

Background

Ticagrelor is a platelet adenosine diphosphate P2Y12 receptor antagonist developed by Aslicon, which has reversible binding, direct action and oral administration, and is mainly used for treating patients with acute coronary syndrome and reducing the incidence rate of thrombotic cardiovascular diseases. The drug was approved by the european union first in 12 months in 2010, 7 months in 2011 and then approved by the FDA, in 2012, ticagrelor was approved to enter china under the trade name of doubly linda. Currently, the two major guidelines of the european cardiology institute have listed the recommended levels of ticagrelor prior to clopidogrel, so patients who cannot use ticagrelor will use clopidogrel.

The structure of ticagrelor has been disclosed by the company asikang in WO9905143 and has the following structural formula:

in the Ticagrelor quality standard, the process impurities mainly comprise the following impurities:

1. ticagrelor chiral isomer impurities having the following structure:

2. an oxygen-substituted impurity having the structure:

3. oxidized impurities having the following structure:

4. polymeric impurities having the structure:

the prior reports about the synthetic route and the preparation method of ticagrelor include that patents such as WO2011036479, WO2012138981, WO2012142983, CN102731467A and CN102675321A all use different patentsThe synthesis route of (a) studies the preparation method of ticagrelor, the overall method is as follows:

according to the existing route, no matter what synthetic route is selected, the preparation process mostly relates to the following intermediate (1S,2S,3R,5S) -3-amino-5- (2-hydroxyethoxy) -1, 2-cyclopentanediol, and the structure of the intermediate is as follows:

the synthesis methods of (1S,2S,3R,5S) -3-amino-5- (2-hydroxyethoxy) -1, 2-cyclopentanediol are reported more, and two synthesis methods, namely a cyclopentadiene method and a D-ribose method, are mainly used according to different starting materials.

Both synthesis methods relate to a compound 1, and the compound 1 is substituted by ethyl bromoacetate, reduced by sodium borohydride and hydrogenated by palladium carbon to obtain an intermediate TKG. In the process of synthesizing ticagrelor from compound 1 through the route shown in fig. 1, unknown impurities are found in the product, no definite research on the unknown impurities is found in the prior art, and no document is reported on the structure, toxicity, separation and synthesis of the unknown impurities. Meanwhile, the content of the unknown impurities in ticagrelor obtained in industrial production cannot be effectively controlled, and the quality of the product is influenced.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides ticagrelor and intermediate impurities thereof and a preparation method. The method synthesizes and purifies the unknown impurities of ticagrelor, analyzes the obtained pure unknown impurities, and determines that the structural formula of the impurities is shown as API dimer, and the impurities are generated by dimer in TKG through a process route. The structure confirmation of the impurities and the pure preparation of the impurities can be used for qualitative and quantitative analysis of the process impurities of ticagrelor, and have an important effect on the quality control of ticagrelor.

In order to achieve the aim, the invention provides a ticagrelor impurity, and the technical scheme is as follows:

an impurity of ticagrelor which is a compound of ticagrelor,

this impurity corresponds to the structural formula of the API dimer.

The invention also aims to provide a ticagrelor intermediate impurity,

this intermediate impurity corresponds to the structural formula of TKG-11 dimer.

The invention also aims to provide a preparation method of ticagrelor impurity, which comprises the following steps:

s1, preparing TKG-9 dimer by the TKG-9 monomer,

TKG-10 dimer is prepared by TKG-9 dimer,

TKG-11 dimer is prepared from TKG-10 dimer,

s2, and preparing the ticagrelor impurity by TKMD substitution, cyclization, TKB substitution and deprotection of the TKG-11 dimer.

Preferably, the ticagrelor impurity is an impurity solution with the purity of more than or equal to 99.9 percent.

The fourth purpose of the invention is to provide a preparation method of ticagrelor intermediate impurities, which comprises the following steps:

s1, preparing TKG-9 dimer by the TKG-9 monomer,

TKG-10 dimer is prepared by TKG-9 dimer,

TKG-11 dimer was prepared from TKG-10 dimer.

Preferably, in step S1, the organic base is added to the organic solution of TKG-9, and the reaction system is reacted at room temperature to prepare TKG-9 dimer.

Further, in step S1, the organic base is selected from sodium tert-butoxide, potassium tert-butoxide, or sodium hydrogen.

Preferably, in step S1, the inorganic salt is added into the organic solution of the TKG-9 dimer, the mixture is uniformly stirred and heated to 45-50 ℃, the reducing agent is added in batches, and the mixture is reacted at 45-50 ℃ to prepare the TKG-10 dimer.

Further, in step S1, sodium borohydride or potassium borohydride is used as the reducing agent.

Preferably, in step S1, the TKG-10 dimer is dissolved in an alcohol solvent at room temperature, nitrogen is replaced for a plurality of times, a metal catalyst is added, the mixture is stirred uniformly, hydrogen is replaced for a plurality of times, and after the replacement is completed, the reaction system is heated to 50-60 ℃ for reaction to prepare the TKG-11 dimer.

Further, in step S1, Pd/C or palladium hydroxide or Raney nickel is used as the metal catalyst.

Preferably, the TKMD substitution reaction in step S2 is:

and (2) dissolving the TKG-11 dimer and the TKMD by using an organic solvent, adding an alkaline solvent, and heating to 90-110 ℃ for reaction to prepare the API-1 dimer.

Further, DMF or DMSO is selected as an organic solvent in the TKMD substitution reaction; the alkaline solvent is triethylamine or DIPEA.

Preferably, the cyclization reaction in step S2 is:

adding sodium nitrite into an API-1 dimer by using glacial acetic acid or hydrochloric acid or sulfuric acid and water as solvents, cooling to-10 ℃, stirring, and reacting to prepare the API-2 dimer.

Preferably, the TKB substitution reaction in step S2 is:

diluting the API-2 dimer with an organic solution, adding TKB, stirring uniformly, adding an alkaline solvent, heating to 30-70 ℃, and reacting to prepare the API-3 dimer.

Further, an organic solvent in the TKB substitution reaction adopts acetonitrile, acetone or DMF, and an alkaline solvent adopts triethylamine, sodium carbonate, potassium carbonate or DIPEA.

Preferably, the deprotection reaction in step S2 is:

and adding an acid solution into the API-3 dimer, and reacting at room temperature to prepare the API dimer, namely the ticagrelor impurity.

Further, the acid solution in the deprotection reaction is a hydrogen chloride/methanol solution or a trifluoroacetic acid/sulfuric acid solution.

The invention has the beneficial effects that:

1) the ticagrelor impurity and the ticagrelor intermediate impurity are synthesized, the pure ticagrelor impurity can be prepared, the structure of the impurity is determined, the impurity can be used for qualitative and quantitative analysis of the ticagrelor process impurity, and the method plays an important role in quality control of ticagrelor.

2) The invention has mild reaction condition and is environment-friendly.

Drawings

Figure 1 is a mass spectrum of ticagrelor impurity.

Detailed Description

The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes and modifications may be made without departing from the principles of the invention and these changes and modifications are to be considered within the scope of the invention.

In the embodiment of the invention:

MS: the mass spectrum is detected by Shimadzu liquid chromatography-mass spectrometry (LCMS-2020).

Example 1 Synthesis of Ticagrelor intermediate impurities

(1) TKG-9 dimer synthesis

At room temperature, N₂t-BuONa (14.7g, 0.153mol) was added in one portion to a toluene solution of TKG-9(150g, 0.382mol) under protection, and the reaction was stirred at room temperature for 18 hours. Filtering the obtained reaction solution by a short silica gel column, concentrating under reduced pressure, purifying the oily substance by the silica gel column, adjusting petroleum ether: eluting ethyl acetate from 10:1 to 1:2, collecting TKG-9 dimer (TLC petroleum ether: ethyl acetate 2:1, and Rf ═ 0.1), and evaporating under reduced pressure to obtain TKG-9 dimer 20.3g。

Or:

at room temperature, N₂t-BuOK (5.4g, 0.134mol) was added in one portion to a toluene solution of TKG-9(150g, 0.382mol) under protection, and the reaction was stirred at room temperature for 15 hours. Filtering the obtained reaction solution by a short silica gel column, concentrating under reduced pressure, purifying the oily substance by the silica gel column, adjusting petroleum ether: the mixture ratio of ethyl acetate was gradient-eluted from 10:1 to 1:2, and a portion of TKG-9 dimer (TLC petroleum ether: ethyl acetate 2:1, Rf ═ 0.1) was collected, and the solvent was evaporated under reduced pressure to give 18.7g of TKG-9 dimer.

Or:

at room temperature, N₂To a toluene solution of TKG-9(150g, 0.382mol), NaH (15.1g, 0.134mol) was added in one portion under protection, and the reaction was stirred at room temperature for 15 hours. Filtering the obtained reaction solution by a short silica gel column, concentrating under reduced pressure, purifying the oily substance by the silica gel column, adjusting petroleum ether: the mixture ratio of ethyl acetate was gradient-eluted from 10:1 to 1:2, and a portion of the TKG-9 dimer (TLC petroleum ether: ethyl acetate 2:1, Rf ═ 0.1) was collected, and the solvent was evaporated under reduced pressure to give 11.2g of the TKG-9 dimer.

(2) TKG-10 dimer synthesis

To a solution of TKG-9 dimer (17g, TKG-9HPLC purity 68%, 15.6mmol) in ethanol (130mL) at room temperature was added anhydrous calcium chloride (3.08g), stirred well and heated to 45-50 ℃. Sodium borohydride (2.94g, 77.7 mmols) is added in portions at 45-50 ℃. Keeping the temperature at 45-50 ℃ for reaction for 4 hours, cooling the reaction to room temperature, dripping 9.4g of acetic acid to quench the reaction, testing the pH of the system to be neutral, adding 50mL of water, stirring for 5 minutes, evaporating ethanol in the system under reduced pressure, extracting the reaction system twice with 150mL of ethyl acetate, combining ethyl acetate layers, and purifying an oily substance obtained by reduced pressure concentration through silica gel column chromatography, wherein the petroleum ether: ethyl acetate 4:1 to 1:2, collecting fractions containing TKG-10 dimer (TLC detection, petroleum ether: ethyl acetate 1:2, Rf 0.2-0.3), concentrating under reduced pressure to obtain 11g of oil (HPLC purity 86%), and separating by column chromatography to obtain 6.2g of TKG-10 dimer (HPLC purity 99%).

Or:

anhydrous magnesium chloride (4.16g) was added to a solution of TKG-9 dimer (17g, TKG-9HPLC purity 68%, 15.6mmol) in isopropanol (150mL) at room temperature, stirred well and heated to 45-50 ℃. Potassium borohydride (3.37g, 62.4mmoL) is added in portions at 45-50 ℃. Keeping the temperature at 45-50 ℃ for reaction for 3.5 hours, cooling the reaction to room temperature, dropping 10.5g of acetic acid to quench the reaction, testing the pH of the system to be neutral, adding 70mL of water, stirring for 5 minutes, evaporating isopropanol in the system under reduced pressure, extracting the reaction system twice with 180mL of ethyl acetate, combining ethyl acetate layers, and purifying an oily substance obtained by reduced pressure concentration through silica gel column chromatography, wherein the petroleum ether: ethyl acetate 4:1 to 1:2, collecting fractions containing TKG-10 dimer (TLC detection, petroleum ether: ethyl acetate 1:2, Rf 0.2-0.3), concentrating under reduced pressure to obtain 11.3g of oil (HPLC purity 86%), and separating by column chromatography to obtain 6.4g of TKG-10 dimer (HPLC purity 99%).

(3) TKG-11 dimer synthesis

0.4g of TKG-10 dimer (0.4g, 0.57mmol) was taken and dissolved in 10g of anhydrous ethanol at room temperature. After 3 times of replacement of nitrogen, 0.04g of 10% Pd/C was added, and after stirring, hydrogen was replaced 5 times. And after the replacement is finished, heating the reaction system to 50-60 ℃ for reaction for 24 hours. Then, the reaction mixture was cooled to room temperature, nitrogen was substituted for 5 times, Pd/C was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to give 0.2g of TKG-11 dimer (HPLC purity: 99%).

Or:

TKG-10 dimer (0.4g, 0.57mmol) was taken and dissolved in 10g of anhydrous methanol at room temperature. After 3 times of nitrogen substitution, 0.086g of Raney nickel (1mmol) was added, and after stirring, hydrogen was substituted 5 times. And after the replacement is finished, heating the reaction system to 50-60 ℃ for reaction for 20 hours. Then, the reaction mixture was cooled to room temperature, nitrogen was substituted for 5 times, raney nickel was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to obtain 0.22g of TKG-11 dimer.

Example 2 Synthesis of ticagrelor (dimer) impurity

1.2g of TKG-11 dimer (2.75mmol) and 1.5g of TKMD (6mmol) were dissolved in 5ml of DMSO, 1.2ml of triethylamine was added, the mixture was heated to 100 ℃ for reaction for 12 hours, ethyl acetate EA was added and the mixture was washed with water, and the organic phase was concentrated to obtain 1.5g of API-1 dimer. And continuously adding 0.4g of sodium nitrite into 1.5g of the API-1 dimer by using 20ml of glacial acetic acid and water as solvents, cooling to 0 ℃, stirring for 4 hours, extracting by using ethyl acetate after the reaction is finished, and concentrating an organic phase to obtain 1.4g of the API-2 dimer. Then, 1.4g of the API-2 dimer was diluted with 20ml of acetonitrile, TKB (0.5g) was added thereto, after stirring the mixture uniformly, 0.6g of triethylamine was added thereto, the mixture was heated to 40 ℃ and reacted for 4 hours, after the reaction, the mixture was concentrated, 15ml of ethyl acetate was added thereto, the mixture was washed with water and brine, and the organic phase was concentrated to obtain 1.7g of the API-3 dimer. Adding 10ml of 3.0M hydrogen chloride/methanol solution into 1.7g of API-3 dimer, reacting at room temperature for 18 hours, quenching with 20 wt% of sodium hydroxide aqueous solution after the reaction is finished, concentrating, and performing column chromatography separation to obtain 1.1g of an API dimer solution (namely ticagrelor impurity prepared by the invention).

Or:

1.2g of TKG-11 dimer (2.75mmol) and 1.31g of TKMD (5.5mmol) were taken, dissolved in 5ml of DMF, 1.5ml of DIPEA was added, the reaction mixture was heated to 90 ℃ for 12 hours, ethyl acetate EA was added and the reaction mixture was washed with water, and the organic phase was concentrated to give 1.51g of API-1 dimer. And continuously adding 0.5g of sodium nitrite into 1.51g of the API-1 dimer by using 20ml of hydrochloric acid and water as solvents, cooling to-5 ℃, stirring for 4 hours, extracting by using ethyl acetate after the reaction is finished, and concentrating an organic phase to obtain 1.42g of the API-2 dimer. Then, 1.42g of the API-2 dimer was diluted with 20ml of acetone, followed by addition of TKB (0.55g), stirring well, addition of 0.72g of sodium carbonate, heating to 30 ℃ for reaction for 4 hours, concentration after the reaction, addition of 20ml of ethyl acetate, washing with water and brine, and concentration of the organic phase to obtain 1.72g of the API-3 dimer. Adding 15ml of 3.0M trifluoroacetic acid/sulfuric acid solution into 1.72g of API-3 dimer, reacting at room temperature for 16 hours, quenching with 20 wt% sodium hydroxide aqueous solution after the reaction is finished, concentrating, and performing column chromatography separation to obtain 1.12g of an API dimer solution (namely ticagrelor impurity prepared by the invention).

As shown in fig. 1, the ticagrelor impurity:

ms (M + 1): 1043, molecular weight 1042, which demonstrates a structural formula corresponding to that shown for the API dimer.

The above description is only a part of the preferred embodiments of the present invention, and the present invention is not limited to the contents of the embodiments. It will be apparent to those skilled in the art that various changes and modifications can be made within the spirit of the invention, and any changes and modifications made are within the scope of the invention.

Claims

1. A ticagrelor intermediate impurity characterized by:

2. A process for preparing a ticagrelor intermediate impurity as claimed in claim 1, comprising the steps of:

(1) preparing TKG-9 dimer sequentially through TKG-9 monomers;

(2) preparing TKG-10 dimer from TKG-9 dimer;

(3) TKG-11 dimer was prepared from TKG-10 dimer.

3. The process for preparing ticagrelor intermediate impurities according to claim 2, wherein:

in the step (1), adding organic alkali into the organic solution of TKG-9, and reacting the reaction system at room temperature to prepare TKG-9 dimer; and/or;

in the step (2), adding inorganic salt into the organic solution of the TKG-9 dimer, uniformly stirring, heating to 45-50 ℃, adding a reducing agent in batches, and reacting at 45-50 ℃ to prepare the TKG-10 dimer; and/or;

in the step (3), the TKG-10 dimer is dissolved in an alcohol solvent at room temperature, nitrogen is replaced for multiple times, a metal catalyst is added, after the nitrogen is uniformly stirred, hydrogen is replaced for multiple times, and after replacement is finished, the reaction system is heated to 50-60 ℃ to react to prepare the TKG-11 dimer.

4. A process for preparing ticagrelor impurity, comprising the steps of:

and (3) preparing ticagrelor impurities by TKMD substitution, cyclization, TKB substitution and deprotection reaction of the TKG-11 dimer.

5. The method of claim 4, wherein the TKMD substitution reaction is:

6. The process for preparing ticagrelor impurity according to claim 4, wherein the cyclization reaction of step S2 is:

7. The method of claim 4, wherein the TKB substitution reaction of step S2 is:

8. The method for preparing ticagrelor impurity according to claim 4, wherein the deprotection reaction in step S2 is:

9. The process for preparing ticagrelor impurity according to claim 4, wherein the ticagrelor impurity is an impurity solution with a purity of 99.9% or more.

10. A ticagrelor impurity characterized by: prepared by the preparation method according to the claims 4-9,

this impurity corresponds to the structural formula of the API dimer.