CN115677597B

CN115677597B - New preparation method of ticagrelor intermediate

Info

Publication number: CN115677597B
Application number: CN202211395626.8A
Authority: CN
Inventors: 邱磊; 戚陈陈; 魏巍; 龙海
Original assignee: Chongqing Puyou Biomedical Co ltd
Current assignee: Chongqing Puyou Biomedical Co ltd
Priority date: 2022-11-09
Filing date: 2022-11-09
Publication date: 2024-03-15
Anticipated expiration: 2042-11-09
Also published as: CN115677597A

Abstract

The invention relates to the technical field of organic synthesis, in particular to a novel preparation method of ticagrelor intermediate. Compared with the scheme disclosed in the prior art, the preparation process is simpler, the yield is higher, and the cost is lower.

Description

New preparation method of ticagrelor intermediate

Technical Field

The invention belongs to the field of organic synthesis, in particular to the field of organic medicine synthesis, and more particularly relates to a novel preparation method of ticagrelor intermediates.

Background

Ticagrelor is an oral selective P2Y12 receptor inhibitor developed by aslicon, uk, and can prevent platelet activation and aggregation caused by ADP, reduce the probability of cardiovascular death, acute Coronary Syndrome (ACS) in patients with myocardial infarction and stroke, and the historical rate of Myocardial Infarction (MI).

Compound v is an important intermediate for the preparation of ticagrelor, the structure of which is shown below:

one route to compound V is given in US 5654285:

the process routes for preparing compound V from thiobarbituric acid are reported in WO2005095358, US2011071290, WO2012138981 and the like,

another method for the preparation of compound V is disclosed in CN103772295 a:

a preparation method is reported in the literature Springer plus,2015,4 (1): 1-11, and comprises the following main steps:

in the process, the bromopropane is firstly cyclized and then butted, and under the synthesis mode, the butting difficulty is high and the yield is low.

Disclosure of Invention

The invention aims to solve the technical problems that the synthesis thought disclosed by America of Ticager Lei Yuan research company is limited, and a synthesis process of looping and then butt joint of bromopropane is adopted, so that the process has high butt joint difficulty and low yield, and the total synthesis yield of an intermediate compound V is low and the process difficulty is high.

In order to solve the problems, the invention discloses a novel preparation method of ticagrelor intermediates, and the synthetic route comprises the following steps:

(1) Thiourea and halogenated propane react and are butted to synthesize the compound I,

x is halogen;

(2) The compound I and malonate synthesize a compound II under the action of alkali,

r1 and R2 are C1-C6 alkyl;

(3) The compound II is nitrified, chloridized and reduced to obtain a compound V,

further, in the step (1), the molar ratio of halogenated propane to thiourea is 1:1-2, preferably 1:1.2.

further, in the step (2), the molar ratio of the compound I, the malonate and the base is 1: 1-2: 1 to 2, preferably 1:1.2:1.2.

further, in the step (2), the alkali may be one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide and sodium methoxide, and preferably sodium methoxide.

Further, in the step (3), the compound II is reacted with fuming nitric acid under the condition of acetic acid to synthesize a compound III.

Further preferably, the addition ratio of the compound II, fuming nitric acid and acetic acid is that of the compound II (calculated by mass m (g)) nitric acid (calculated by volume v (ml): acetic acid (calculated as volume v (ml)) =1: 0.5 to 2:1 to 4, preferably 1:1:2.

further, in the step (3), the molar ratio of the compound iii to the chlorinating agent is 1:2 to 5, preferably 1:2.5.

further, in the step (3), the chlorinating agent may be one or more of phosphorus oxychloride, phosgene, sulfonyl chloride, oxalyl chloride and thionyl chloride, and is preferably phosphorus oxychloride.

Further, in the step (3), the compound IV is reduced by adopting a hydrogenation reduction mode of an immobilized metal catalyst to obtain a compound V, wherein the carrier of the catalyst is selected from one of alumina, silicon dioxide or activated carbon, and preferably the activated carbon; the catalyst is selected from one of platinum and nickel palladium.

Further, in the step (3), the mass ratio of the compound IV to the catalyst is 0.01-0.1: 1.

the invention breaks through the thinking formula in the prior art, adopts a synthesis mode of firstly butting halogenated propane and then cyclizing, and surprisingly discovers that the process operation can be simplified, and the product yield can be obviously improved. Meanwhile, the invention adopts the mode of hydrogenation reduction of the nitro by the solid metal catalyst, thereby not only greatly reducing the generation of wastewater, but also remarkably improving the utilization rate of the catalyst and reducing the cost.

Detailed Description

The present invention will be further elucidated with reference to the following embodiments, which should be understood as merely illustrative of the invention and not as limiting the scope of the invention.

Example 1

Synthesis of Compound I

To the reactor were added chloropropane (39.27 g,0.5 mol) and thiourea (45.7 g,0.6 mol), water (400 ml) and heated to reflux for 3 to 4 hours. After the completion of the reaction, the reaction system was evaporated, and ethanol (200 ml) was added with the dry solvent three times.

Ethanol (100 ml) and acetone (300 ml) were then added, and the mixture was stirred for 1 hour. Cooling to crystallize, filtering the crystallized solid, and drying the product under high vacuum overnight to obtain compound i (55.32 g, 0.4638 mol) in 93.6% yield.

Example 2

Synthesis of Compound II

Sodium methoxide (32.4 g;0.6 mol) and dimethyl malonate (79.1 g,0.5 mol) were added to the reactor, methanol (200 ml) was added and dissolved with stirring, and the temperature was raised to 50-55℃to react for 3-4 hours. After the reaction is completed, the system is cooled to 0-5 ℃ and stirred for 30-45min for crystallization.

The precipitated crystals were filtered, washed with pre-chilled methanol (50 ml) and dried under vacuum at 50-55℃for 2-3 hours to give compound II (83.15 g, 0.4476 mol) in 89.3% yield.

Example 3

Synthesis of Compound III

The reactor was cooled to 0deg.C, to which was added Compound II (74.5 g,0.4 mol), fuming nitric acid (75 ml) and acetic acid (150 ml) were added and dissolved with stirring, and the mixture was slowly warmed to room temperature to react for 1.5 hours. Ice water (120 ml) is added into the system after the reaction is finished, the temperature is controlled to be not higher than 30 ℃, and a large amount of crystals are separated out. The mixture was filtered, and the cake was washed twice with water (50 mL) and dried to give compound III (77 g,0.333 mol) in 83.3% yield.

Example 4

Synthesis of Compound IV

To the reactor was added compound III (92.5 g,0.4 mol), phosphorus oxychloride (153.3 g,1 mol) and triethylamine (40.5 g,0.4 mol), and the mixture was refluxed at a temperature of 1.5 hours. After completion of the reaction, ice water (50 mL) was added to the system and stirred for 20 minutes, extraction was performed three times with methylene chloride (100 mL), the organic phases were combined, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give compound iv (92.34 g,0.34 mol) in 86.1% yield.

Example 5

Synthesis of Compound V

To the high pressure reactor was added 5% palladium on carbon (4 g) and compound IV (80.43 g,0.3 mol), methanol (200 ml) was added and mixed with stirring. The nitrogen replaces the air in the kettle for three times, hydrogen is filled until the pressure in the kettle reaches 0.8-1 Mpa, the temperature of the system is raised to 40-45 ℃, and the system is stirred for 4 hours.

After the reaction, slowly cooling to room temperature, discharging hydrogen, filtering the catalyst, flushing the filter cake with methanol, recovering the dry solvent from the filtrate under reduced pressure, and obtaining compound V (63.15 g,0.265 mol) in 88.4% yield and 97.1% purity in liquid phase.

Examples 6 to 9

Other conditions are the same as in example 1, except that the molar ratio of halopropane to thiourea is changed, the kind of halopropane, and the reaction conditions and yields of example 1 and examples 6 to 9 are shown in Table 1.

TABLE 1 different conditions and results for example 1, examples 6-9

Examples	Halopropanes: thiourea	Halogenated propane species	Yield/%
				1	1:1.2	Chloropropane	93.6
6	1:1	Chloropropane	92.8
				7	1:2	Chloropropane	91.1
8	1:1.2	Bromopropane	91.5
				9	1:1.2	Iodopropane	89.2

Examples 10 to 12

Other conditions were the same as in example 2, except that the molar ratio of compound I, malonate to base was varied, the malonate species; the reaction conditions and yields of example 2 and examples 10-12 are detailed in Table 2.

TABLE 2 different conditions and results for example 2, examples 10-12

Examples	Compound i: malonic ester: alkali	Malonic ester species	Yield/%
				2	1:1.2:1:2	Dimethyl ester	89.3
10	1:1:1	Dimethyl ester	86.7
				11	1:2:2	Dimethyl ester	88.2
12	1:1.2:1:2	Diethyl ester	88.5

Examples 13 to 10

Other conditions are the same as in example 3, except that the mass-to-volume ratio of compound II, fuming nitric acid, acetic acid is changed, and the reaction conditions and yields of example 3 and examples 13 to 14 are shown in Table 3.

TABLE 3 different conditions and results for example 3, examples 13-14

Examples 15 to 18

Other conditions are the same as in example 4 except that the molar ratio of compound III to chlorinating agent, the type of chlorinating agent, the reaction conditions and results of example 4 and examples 15-18 are detailed in Table 4.

TABLE 4 different conditions and results for example 4, examples 15-18

Examples 19 to 21

Other conditions are the same as in example 5, except that the mass ratio of the compound IV to the catalyst, the kind of the catalyst, the reaction conditions and the results of example 5 and examples 19 to 21 are shown in Table 5.

TABLE 5 different conditions and results for example 5, examples 19-21

Comparative example

Comparative example 1

Sodium methoxide (32.4 g;0.6 mol) was added to the reactor, thiourea (38.1 g,0.5 mol) and dimethyl malonate (79.3 g,0.6 mol) were added, methanol (200 ml) was added and dissolved with stirring, and the temperature was raised to 50-55℃to react for 3-4 hours. After the reaction is completed, the system is cooled to 0-5 ℃ and stirred for 30-45min for crystallization.

The precipitated crystals were filtered, washed with pre-chilled methanol (50 ml) and dried under vacuum at 50-55deg.C for 2-3 hours to give 6-hydroxy-2-mercaptopyrimidin-4-one (59.89 g, 0.418 mol) in 83.1% yield.

Comparative example 2

To the reactor were added chloropropane (39.27 g,0.5 mol) and 6-hydroxy-2-mercaptopyrimidin-4-one (86.49 g,0.6 mol), water (400 ml) and heated to reflux for 3 to 4 hours. After the completion of the reaction, the reaction system was evaporated, and ethanol (200 ml) was added with the dry solvent three times.

Ethanol (100 ml) and acetone (300 ml) were then added, and the mixture was stirred for 1 hour. Cooling to crystallize, filtering the crystallized solid, and drying the product under high vacuum overnight to obtain compound II (72.34 g, 0.3838 mol) in 77.6% yield.

Comparative examples 3 to 5

Other conditions were the same as in comparative example 1 except that the molar ratio of thiourea, malonate to base, the molar ratio of the malonate species, 6-hydroxy-2-mercaptopyrimidin-4-one to halopropane, the halopropane species, the reaction conditions and yields of comparative example 1 and comparative examples 3-5 were as detailed in Table 6.

TABLE 6 different conditions and results for comparative example 1, comparative examples 3-5

Examples	Thiourea, malonate and base	Malonic ester species	Yield/%
				1	1:1.2:1:2	Dimethyl ester	83.1
3	1:1:1	Dimethyl ester	79.8
				4	1:2:2	Dimethyl ester	82.3
5	1:1.2:1:2	Diethyl ester	81.7

Comparative examples 6 to 9

Other conditions are the same as comparative example 2, the molar ratio of halopropane to 6-hydroxy-2-mercaptopyrimidin-4-one, the kind of halopropane, the reaction conditions and yields of comparative example 2 and comparative examples 6-9 are shown in Table 7.

TABLE 7 different conditions and results for comparative example 2, comparative examples 6-9

It should be noted that the foregoing merely illustrates the technical idea of the present invention and is not intended to limit the scope of the present invention, and that a person skilled in the art may make several improvements and modifications without departing from the principles of the present invention, which fall within the scope of the claims of the present invention.

Claims

1. The novel preparation method of the ticagrelor intermediate is characterized in that the synthetic route comprises the following steps:

x is halogen;

r1 and R2 are C1-C6 alkyl;

。

2. the novel process for the preparation of ticagrelor intermediate according to claim 1, wherein in step (1), the molar ratio of halogenated propane to thiourea is 1:1-2.

3. The novel process for the preparation of ticagrelor intermediate according to claim 1, characterized in that in step (1), the molar ratio of halogenated propane to thiourea is 1:1.2.

4. the novel process for the preparation of ticagrelor intermediates according to claim 1, characterized in that in step (2), the molar ratio of compound i, malonate to base is 1: 1-2: 1-2.

5. The novel process for the preparation of ticagrelor intermediates according to claim 1, characterized in that in step (2), the molar ratio of compound i, malonate to base is 1:1.2:1.2.

6. the novel preparation method of ticagrelor intermediate according to claim 1, wherein in step (2), the base is one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide and sodium methoxide.

7. The novel process for the preparation of ticagrelor intermediate according to claim 1, wherein in step (2), the base is sodium methoxide.

8. The novel preparation method of ticagrelor intermediate according to claim 1, wherein in step (3), the compound ii is reacted with fuming nitric acid under acetic acid condition to synthesize compound III.

9. The novel preparation method of ticagrelor intermediate according to claim 8, wherein the addition ratio of the compound II, fuming nitric acid and acetic acid is 1g of the compound II, 0.5-2 ml of nitric acid and 1-4 ml of acetic acid.

10. The novel process for preparing ticagrelor intermediate according to claim 8, wherein the addition ratio of the compound II, fuming nitric acid and acetic acid is 1g of compound II, 1ml of nitric acid and 2ml of acetic acid.

11. The novel process for the preparation of ticagrelor intermediates according to claim 1, characterized in that in step (3), the molar ratio of compound iii to chlorinating agent is 1: 2-5.

12. The novel process for the preparation of ticagrelor intermediates according to claim 1, characterized in that in step (3), the molar ratio of compound iii to chlorinating agent is 1:2.5.

13. the novel preparation method of ticagrelor intermediate according to claim 1, wherein in the step (3), the chlorinating agent is one or more of phosphorus oxychloride, phosgene, sulfonyl chloride, oxalyl chloride and thionyl chloride.

14. The novel process for the preparation of ticagrelor intermediates according to claim 1, characterized in that in step (3), the chlorinating agent is phosphorus oxychloride.

15. The novel preparation method of ticagrelor intermediate according to claim 1, wherein in step (3), compound IV is reduced by hydrogenation reduction with an immobilized metal catalyst to obtain compound V, wherein the carrier of the catalyst is selected from one of alumina, silica or activated carbon.

16. The novel preparation method of ticagrelor intermediate according to claim 1, wherein in step (3), compound IV is reduced by hydrogenation reduction with an immobilized metal catalyst to obtain compound V, wherein the carrier of the catalyst is activated carbon.

17. The novel preparation method of ticagrelor intermediate according to claim 1, wherein in the step (3), the compound IV is reduced by hydrogenation reduction with an immobilized metal catalyst, and the catalyst is selected from one of platinum and nickel palladium.