CN115785058A - Method for synthesizing ticagrelor five-membered ring intermediate - Google Patents

Abstract

The invention discloses a method for synthesizing a ticagrelor five-membered ring intermediate, which comprises the following steps: step1, amino protection: taking the compound 1 as a starting material, and reacting to prepare a compound 2 protected by benzyloxycarbonyl; step2, ring closing reaction: reacting the compound 2 with ethylene oxide to prepare a compound 3; step3, deprotection reaction: carrying out hydrogen deprotection reaction on the compound 3 to prepare a compound 4; step4, salt forming reaction: the chemical formula 4 reacts with L-tartaric acid to form salt, and the compound 5 is prepared. According to the invention, the compound 2 is directly reacted with ethylene oxide to obtain the compound 3, compared with the prior art, the route is shorter, the atom economy is better, the generation of a large amount of waste water and waste liquid is avoided, and the method is suitable for producing the ticagrelor intermediate.

Description

A method for synthesizing ticagrelor five-membered ring intermediate

technical field

The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a five-membered ring intermediate of ticagrelor.

Background technique

Ticagrelor is a platelet aggregation inhibitor, mainly used for acute coronary syndrome (unstable angina, non-ST-segment elevation myocardial infarction or ST-segment elevation myocardial infarction), including drug therapy and percutaneous coronary Patients treated with arterial intervention (PCI) can reduce thrombotic cardiovascular events.

There have been many reports on the preparation methods of ticagrelor. In the known preparation methods of ticagrelor, compound 5 is a key intermediate for the synthesis of ticagrelor, and its chemical structural formula is:

The specific preparation route of compound 5 is as follows: compound 2 was reacted with ethyl bromoacetate in anhydrous solvent under the action of strong base to obtain compound 6, and compound 6 was reduced by sodium borohydride to obtain compound 7. Compound 7 was deprotected and salted to obtain Compound 5.

Compound 7 is obtained by reduction of compound 6, and a large amount of hydrogen gas is generated during the reaction process, which poses a high safety risk. The synthesis of compound 6 needs to be carried out in a strong base and anhydrous solvent, the reaction conditions are relatively harsh, the post-reaction treatment process is cumbersome, and a large amount of waste water and waste liquid are generated.

Contents of the invention

The object of the present invention is to provide a method for synthesizing the five-membered ring intermediate of ticagrelor, which overcomes the deficiencies in the prior art. The preparation method has a shorter route, better atom economy, and avoids the generation of a large amount of waste water and waste liquid , suitable for the production of ticagrelor intermediates.

The present invention is implemented through the following technical solutions:

A method for synthesizing a five-membered ring intermediate of ticagrelor, comprising the following steps:

Step1, amino protection: using compound 1 as the starting material, react to prepare compound 2 protected by benzyloxycarbonyl;

Step2, ring closure reaction: compound 2 reacts with ethylene oxide to prepare compound 3;

Step3, deprotection reaction: compound 4 is prepared by hydrogen deprotection reaction of compound 3;

Step4. Salt formation reaction: chemical formula 4 reacts with L-tartaric acid to form a salt to prepare compound 5.

Further, Step1 amino protection:

摩尔当量为1.0～1.5eq，优选1.2eq；反应原料还包括碳酸钠，碳酸钠摩尔当量为1.5～3eq，优选1.8eq。Compound 1 reacts with compound 8 benzyl chloroformate to prepare compound 2, and the structural formula of compound 8 is

The molar equivalent is 1.0-1.5eq, preferably 1.2eq; the reaction raw material also includes sodium carbonate, and the molar equivalent of sodium carbonate is 1.5-3eq, preferably 1.8eq.

The reaction solvent is a methanol-water mixed solution, wherein the mass of methanol is 5 to 20 times the mass of the raw material compound 1, preferably 10 to 15 times; the mass of water is 1 to 10 times the mass of the raw material compound 1, and 4 to 6 times the mass of the raw material compound 1 is preferred. times; the reaction temperature is 0-40°C, preferably 15-25°C.

Further, the specific operation steps of Step1 amino protection are as follows:

Add compound 1 and methanol to the reaction bottle, stir to dissolve, add sodium carbonate and water, cool down to 0-5°C, add benzyl chloroformate dropwise under stirring, control the temperature during the dropwise addition to not exceed 25°C, and react for 2 hours below 25°C , filtered, rinsed with methanol, concentrated the methanol, extracted the remaining aqueous phase with dichloromethane, combined the dichloromethane layers and concentrated. The concentrated residue was recrystallized from toluene and dried in vacuo to obtain compound 2 as a white solid.

Further, Step2 ring-closing reaction:

The molar equivalent of ethylene oxide is 0.8-1.5, preferably 1.0-1.1.

The reaction solvent is tetrahydrofuran or toluene, and the solvent mass is 1 to 10 times, preferably 2 to 5 times, the mass of the raw material compound 2; the reaction temperature is 50 to 150°C, preferably 70 to 120°C; the reaction vessel is an autoclave or a sealed tube, preferably Autoclave.

Further, the specific operation steps of Step2 ring-closing reaction are as follows:

Add compound 2, tetrahydrofuran and ethylene oxide into the autoclave, seal the autoclave, raise the temperature to 50-150°C for 8 hours, cool down to room temperature, spin the reaction solution to dryness, and purify the spin-dried residue by column chromatography to obtain The off-white solid is compound 3.

Further, Step3 deprotection reaction

The reaction also includes a catalyst, the catalyst is palladium carbon, and its mass is 1% to 5% of the mass of the raw material compound 3, preferably 3%.

The reaction solvent is methanol, and its mass is 1.5-5 times, preferably 2-3 times, the mass of the raw material compound 3; the reaction temperature is 10-50°C, preferably 20-30°C.

Further, the specific operation steps of Step3 deprotection reaction are as follows:

Add methanol, compound 3 and 5% palladium carbon into the autoclave, seal the autoclave, first replace with nitrogen, then pressurize with hydrogen to 1.0MPa, stir and react at room temperature for 4 hours, filter the reaction solution, spin dry to get a light yellow solid which is the compound 4.

Further, Step4 salt-forming reaction

The molar equivalent of L-tartaric acid is 1.0-2.0 eq, preferably 1.4-1.6 eq.

The reaction solvent is an ethanol-ethyl acetate mixed solution, wherein the quality of ethanol is 2 to 4 times, preferably 2.5 to 3.5 times that of the raw material compound 4; the quality of ethyl acetate is 5 to 10 times, preferably 7 to 8 times that of the raw material compound 4 ; The reaction temperature is 50-80°C, preferably 60-70°C.

Further, the specific operation steps of Step4 salt-forming reaction are as follows:

Add ethanol and ethyl acetate to the reaction kettle, add compound 4 and L-tartaric acid, heat up to 50-80°C for 2 hours, slowly cool down to add seed crystals, then slowly cool down to 0°C, stir for 1h, filter, and vacuum dry to obtain white The solid is compound 5.

Beneficial effects of the present invention: the present invention uses compound 2 to directly react with ethylene oxide to obtain compound 3. Compared with the prior art, the route is shorter, the atom economy is better, and the generation of a large amount of waste water and waste liquid is avoided. It is suitable for Production of ticagrelor intermediates.

Detailed ways

The technical solution of the present invention will be described in further detail below in conjunction with specific examples, but the scope of protection of the present invention is not limited to the following examples.

Example 1

Synthesis of compound 2

Add 12.6g (72.7mmol) compound 1 in reaction bottle, add 181g methanol, stir to dissolve, add 15.4g (145.4mmol) sodium carbonate, add 55g water, cool to 0～5 ℃, dropwise add 14.9g ( 87.2mmol) benzyl chloroformate, the dropwise addition process controls the temperature not to exceed 25°C, reacts below 25°C for 2 hours, filters, rinses with methanol, concentrates methanol, and extracts the remaining aqueous phase with dichloromethane (48g, 19g each extracted once ), the dichloromethane layers were combined and concentrated. The concentrated residue was recrystallized from 16 g of toluene and dried under vacuum at 50° C. to obtain a white solid (20.8 g, yield 93%, purity 99%).

MS:m/z＝308[M]+

¹ H NMR (400MHz, DMSO) δ7.48–7.22 (m, 5H), 6.53 (d, J=8.2Hz, 1H), 5.33 (s, 1H), 5.02 (s, 2H), 4.39 (dd, J =25.9,5.9Hz,2H),3.98(s,1H),3.82(s,1H),2.15–2.02(m,1H),1.58(d,J=13.8Hz,1H),1.34(s,3H) ,1.20(s,3H).

Example 2

Synthesis of compound 3

Add compound 2 (6.14g, 20mmol) to the autoclave, add 18g tetrahydrofuran, add ethylene oxide (0.88g, 20mmol), seal the autoclave, heat up to 100°C for 8 hours, cool to room temperature, and react The liquid was spin-dried, and the spin-dried residue was purified by column chromatography to obtain an off-white solid (3.7 g, yield 53%, purity 96%).

MS:m/z＝352[M]+

¹ H NMR (400MHz, DMSO) δ7.46–7.26 (m, 5H), 6.86 (d, J=7.9Hz, 1H), 5.02 (s, 2H), 4.71 (s, 1H), 4.44 (dd, J ＝24.5,6.1Hz,2H),3.90–3.75(m,2H),3.57–3.37(m,4H),2.17–2.04(m,1H),1.80–1.65(m,1H),1.35(s,3H ),1.21(s,3H).

Example 3

Synthesis of Compound 4

Add methanol (10g) to the autoclave, add compound 3 (2.3g, 6.5mmol), add 5% palladium carbon (0.07g), seal the autoclave, first replace with nitrogen, then pressurize to 1.0MPa with hydrogen, and stir at room temperature React for 4 hours. The reaction solution was filtered and spin-dried to obtain a light yellow solid (1.4 g, yield 96%, purity 95%).

MS:m/z＝218[M]+

¹ H NMR (400MHz, DMSO) δ4.51(d, J=6.0Hz, 1H), 4.32(d, J=6.1Hz, 1H), 3.78–3.68(m, 1H), 3.57–3.41(m, 4H ),3.11–3.00(m,1H),2.06–1.94(m,1H),1.64–1.53(m,1H),1.32(s,3H),1.21(s,3H).

Example 4

Synthesis of compound 5

Add ethanol (4.9g) and ethyl acetate (11.4) to the reaction kettle, add compound 4 (1.5g, 5.8mmol), add L-tartaric acid (1.3g, 8.7mmol), heat up to 70 ° C for 2 hours, Slowly cool down to 60°C and add seed crystals, then slowly cool down to 0°C, stir for 1 h, filter, and dry in vacuo to obtain a white solid (1.8 g, yield 86%, purity 99%).

MS:m/z＝218[M]+

¹ H NMR (500MHz, DMSO) δ4.62–4.58(m,2H),3.93–3.86(m,4H),3.56–3.43(m,5H),3.40(dd,J＝6.3,3.2Hz,1H) ,2.20–2.11(m,1H),1.87(d,J＝14.4Hz,1H),1.36(s,3H),1.24(s,3H).

It can be seen from the examples that the technical scheme of the present invention has shorter routes, better atom economy, and avoids the generation of a large amount of waste water and waste liquid, and is suitable for the production of ticagrelor intermediates.

Finally, it should be noted that: the above-described embodiments only express several implementations of the present invention, and are not intended to limit the invention of the invention. For those of ordinary skill in the art, without departing from the concept of the present invention, Any modifications, equivalent replacements, improvements, etc., should be included within the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

Claims (9)

1. a method for synthesizing the five-membered ring intermediate of ticagrelor, is characterized in that, comprises the following steps:

Step1, amino protection: using compound 1 as the starting material, react to prepare compound 2 protected by benzyloxycarbonyl; Step2, ring closure reaction: compound 2 reacts with ethylene oxide to prepare compound 3; Step3, deprotection reaction: compound 4 is prepared by hydrogen deprotection reaction of compound 3; Step4. Salt formation reaction: chemical formula 4 reacts with L-tartaric acid to form a salt to prepare compound 5. 2. the method for synthesizing the five-membered ring intermediate of ticagrelor according to claim 1, is characterized in that, Step1 amino protection is specifically: compound 1 reacts with compound 8 benzyl chloroformate to prepare compound 2, the structural formula of compound 8 for

The molar equivalent is 1.0-1.5eq, preferably 1.2eq; the reaction raw material in Step1 also includes sodium carbonate, and the molar equivalent of sodium carbonate is 1.5-3eq, preferably 1.8eq. 3. the method for synthesizing the five-membered ring intermediate of ticagrelor according to claim 1, is characterized in that, in Step1, reaction solvent is methanol-water mixed solution, and wherein, methanol quality is 5～20 of raw material compound 1 quality. times, preferably 10 to 15 times; the quality of water is 1 to 10 times that of the raw material compound 1, preferably 4 to 6 times; the reaction temperature is 0 to 40°C, preferably 15 to 25°C. 4. The method for synthesizing the five-membered ring intermediate of ticagrelor according to claim 1, characterized in that the molar equivalent of ethylene oxide in the Step2 ring closure reaction is 0.8 to 1.5, preferably 1.0 to 1.1. 5. the method for synthesizing the five-membered ring intermediate of ticagrelor according to claim 1, is characterized in that, in Step2, reaction solvent is tetrahydrofuran or toluene, and solvent quality is 1～10 times of raw material compound 2 quality, preferably 2 ~5 times; the reaction temperature is 50-150°C, preferably 70-120°C; the reaction vessel is an autoclave or a sealed tube, preferably an autoclave. 6. the method for synthesizing ticagrelor five-membered ring intermediate according to claim 1, is characterized in that, Step3 deprotection reaction also comprises catalyzer, and catalyzer selects palladium charcoal for use, and its quality is 1%～of raw material compound 3 quality 5%, preferably 3%. 7. the method for synthesizing the five-membered ring intermediate of ticagrelor according to claim 1, is characterized in that, in Step3, reaction solvent is methanol, and its quality is 1.5～5 times of raw material compound 3 quality, preferably 2～5. 3 times; the reaction temperature is 10-50°C, preferably 20-30°C. 8. The method for synthesizing the five-membered ring intermediate of ticagrelor according to claim 1, characterized in that the molar equivalent of L-tartaric acid in the Step4 salt-forming reaction is 1.0 to 2.0 eq, preferably 1.4 to 1.6 eq. 9. the method for synthesizing ticagrelor five-membered ring intermediate according to claim 1, is characterized in that, reaction solvent is ethanol-ethyl acetate mixed solution in Step4, and wherein, ethanol quality is 2～2 of raw material compound 4. 4 times, preferably 2.5 to 3.5 times; the mass of ethyl acetate is 5 to 10 times, preferably 7 to 8 times that of the raw material compound 4; the reaction temperature is 50 to 80°C, preferably 60 to 70°C.