Preparation method of key intermediate of ticagrelor

Abstract

The invention discloses a method for preparing a key intermediate I of ticagrelor, wherein compound II is first reacted with ethylene carbonate under an organic solvent and alkaline conditions to obtain compound IV, and then hydrolyzed under an organic solvent and alkaline conditions to obtain compound I. The synthetic route of the invention has cheap and readily available synthetic raw materials, mild reaction conditions, high yield, low cost, safety and environmental protection, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a method for preparing a key intermediate I of ticagrelor. Background Art

[0002] Ticagrelor has the following structure and its chemical name is (1S,2S,3R,5S)-3-[7-(1R,2S)-2-[3,4-difluorophenylcyclopropylamino]-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol:

[0003]

[0004] Ticagrelor is the first reversible combined oral P2Y12 adenosine diphosphate receptor antagonist, which has a significant inhibitory effect on ADP-induced platelet aggregation and is mainly used to treat patients with acute coronary syndrome and reduce the incidence of thrombotic cardiovascular disease. The compound was developed by AstraZeneca and passed the approval for marketing in the EU and the US in 2010 and 2011 respectively. It was approved for entry into China in 2012 under the trade name of Brilinda.

[0005] Existing reports on the synthesis method of ticagrelor mainly include: WO2011036479, WO2012138981, WO2012142983, CN101143864A, CN102731467A, CN102659815A, CN102675321, etc., and these methods generally involve the following intermediates:

[0006]

[0007] A method for synthesizing the above-mentioned compound I using D-ribose as a starting material is disclosed in the journal literature (Bioorganic & Medicinal Chemistry Letters) and patents WO2013092900 and CN201510289960. The method has a long route and a low overall yield. The specific route is as follows:

[0008]

[0009] WO2010069408, WO2012063126, etc. disclose a method for preparing the above-mentioned compound I using a cyclopentene derivative as a starting material. This method has a long route, a low yield, and requires the use of highly toxic compound osmium tetroxide, which poses a safety risk and is not suitable for industrial production. The specific route is as follows:

[0010]

[0011] CN103588750B discloses a method for preparing the above-mentioned compound I. Although the method has a short route, the starting material dicyclopentane is expensive and difficult to obtain, and needs to undergo chiral separation, with low yield and high cost. In addition, the method also uses sodium azide as a reaction raw material, which has a high safety risk and is not conducive to industrial production. The specific route is as follows:

[0012]

[0013] CN106496179A, CN106496180A, etc. disclose a method for preparing the above-mentioned compound I using oxime and cyclopentadiene as starting materials. This method also has the disadvantages of a long route and low yield. In addition, the highly toxic compound osmium tetroxide is also used, which has a high safety risk and is not suitable for industrial production. The specific route is as follows:

[0014]

[0015] CN103539773A discloses a method for preparing the above-mentioned compound I. The method has a short route, but has the disadvantage of low yield (25-39%), and the palladium carbon catalyst is selected for catalytic hydrogenation in the deprotection reaction, which is expensive and dangerous, and is also not suitable for industrial production. The specific route is as follows:

[0016]

[0017] In summary, the current methods for synthesizing the above-mentioned compound I generally have defects such as long routes, low yields, or expensive materials used, high risks, and no stereoselectivity. Therefore, a better method is still needed to meet the production needs of ticagrelor. Summary of the invention

[0018] In view of the problems existing in the above-mentioned prior art, the present application proposes a method for preparing a key intermediate compound I of ticagrelor, and the preparation method thereof is as follows:

[0019]

[0020] The specific preparation process includes:

[0021] Step a:

[0022] Compound II reacts with ethylene carbonate in the presence of organic solvent 1 and base 1 to obtain compound IV;

[0023] Step b:

[0024] Compound IV is hydrolyzed in the presence of an organic solvent 2 and a base 2 to give compound I.

[0025] In some embodiments, the organic solvent in step a is selected from ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, toluene, methyl tert-butyl ether, chloroform, methyltetrahydrofuran, acetone or N,N-dimethylformamide; preferably, the organic solvent in step a is tetrahydrofuran.

[0026] In some embodiments, the base in step a is selected from potassium carbonate, potassium hydroxide, potassium tert-butoxide, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide or sodium hydride; preferably, the base in step a is potassium hydroxide.

[0027] In some embodiments, the molar ratio of compound II in step a to ethylene carbonate is 1:1.0-2.5; preferably, the molar ratio of compound II in step a to ethylene carbonate is 1.0-1.6. Further preferably, the molar ratio of compound II in step a to ethylene carbonate is 1:1.6.

[0028] In some embodiments, the reaction time of step a is 1-5 h.

[0029] In some embodiments, the molar ratio of compound II in step a to the base is 1:1.0-3.0; preferably, the molar ratio of compound II in step a to the base is 1:1.1-1.8; further preferably, the molar ratio of compound II in step a to the base is 1:1.8.

[0030] In some embodiments, the reaction temperature of step a is 0-120°C; preferably, the reaction temperature of step a is 40-80°C.

[0031] In some embodiments, the organic solvent in step b is selected from tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane or acetonitrile; preferably, the organic solvent in step a is ethyl acetate.

[0032] In some embodiments, the base in step b is selected from sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium amide; preferably, the base in step a is potassium hydroxide.

[0033] In some embodiments, the molar ratio of compound IV to base in step b is 1:1.0-2.5; preferably, the molar ratio of compound IV to base in step b is 1:1.0-1.5; further preferably, the molar ratio of compound IV to base in step b is 1:1.5.

[0034] In some embodiments, the reaction temperature of step b is 50-160°C; preferably, the reaction temperature of step b is 80-120°C.

[0035] In some embodiments, step a comprises a post-treatment step: extraction with ethyl acetate, washing with saturated sodium chloride, concentration, and recrystallization with ethyl acetate-petroleum ether to obtain compound IV.

[0036] In some embodiments, step b includes a post-treatment step: extraction with dichloromethane, washing with saturated sodium chloride, concentration, and recrystallization with ethanol to obtain compound I.

[0037] In some embodiments, the preparation method of the key intermediate compound I of ticagrelor is:

[0038] Step a: At 70°C, 800g of compound II was dissolved in 6L of tetrahydrofuran, and 591g of potassium hydroxide (1.8eq) and 290g (1.6eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 2h, 4L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV;

[0039] Step b: Dissolve 500 g of compound IV in 2.5 L of ethyl acetate, add 104 g of potassium hydroxide (1.3 eq), heat the reaction solution to 70 ° C and stir for 4 h, add 1.5 L of water, extract with ethyl acetate, wash with saturated sodium chloride, concentrate, and recrystallize with ethanol to obtain pure compound I.

[0040] Beneficial effects achieved by the present invention:

[0041] 1. The present invention uses ethylene carbonate for the reaction, which is more environmentally friendly and milder in nature, and the operation is simpler in the process of preparing compound IV, and the yield can be as high as 86%-94%, achieving unexpected technical effects;

[0042] 2. In the deamino protecting group reaction, the present invention avoids the expensive and dangerous palladium catalysts, and selects organic solvents and bases for deprotection, and also achieves a yield similar to that of palladium catalysts, about 84%-94%;

[0043] 3. Through the synthesis process of the present invention, the total yield of the route for preparing compound I from the starting compound II is about 88%, which is simpler and has lower production cost than the prior art.

[0044] In summary, this synthesis process uses cheap and readily available starting materials, the synthesis process steps are short, the reaction conditions are relatively mild, and high-purity compound I is obtained with high yield, effectively reducing the production cost of the key intermediate of ticagrelor. DETAILED DESCRIPTION

[0045] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

[0046] Nuclear magnetic resonance (1HNMR) shift (δ) is given in parts per million (ppm); Nuclear magnetic resonance (1HNMR) is measured using a Bruker AVANCE-300 NMR spectrometer, the measurement solvent is deuterated chloroform (CDCl3-d6), the internal standard is tetramethylsilane (TMS), and the chemical shift is given in 10-6 (ppm).

[0047] Example 1 Preparation of Compound IV

[0048]

[0049] At 0°C, 2 kg of compound II was dissolved in 15 L of tetrahydrofuran, and 0.8 kg of potassium tert-butoxide (1.1 eq) and 0.64 kg (1.1 eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 5 h, 10 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (2.1 kg, yield 90%).

[0050] 1 H-NMR (300MHz, DMSO-d6): δ7.85(s,1H),7.30-7.45(m,3H),7.07(m,1H),7.69(t,1H),5.88(d,1H),5.10(m,2H),4.59(m,1H) ,4.52(m,1H),4.13(m,1H),3.89(m,1H),3.73(m,1H),3.60(m,1H),2.19(m,1H),1.82(d,1H),1.41(s,3H),1.27(s,3H).EIMS m / z 352.2([M+H] + ).

[0051] Example 2 Preparation of Compound IV

[0052]

[0053] At 25°C, 1000g of compound II was dissolved in 5L of ethyl acetate, 436g of potassium tert-butoxide (1.2eq) and 290g (1.0eq) of ethylene carbonate were added in sequence, the reaction solution was stirred for 4h, 5L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (1024g, yield 87%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0054] Example 3 Preparation of Compound IV

[0055]

[0056] At 40°C, 500g of compound II was dissolved in 4L of acetonitrile, and 219g of potassium tert-butoxide (1.5eq) and 139g (1.2eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 3h, 10L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (515g, yield 89%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0057] Example 4 Preparation of Compound IV

[0058]

[0059] At 30°C, 600g of compound II was dissolved in 4L of dichloromethane, and 228g of potassium tert-butoxide (1.3eq) and 150g (1.1eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 3h, 2L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (611g, yield 88%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0060] Example 5 Preparation of Compound IV

[0061]

[0062] At 80°C, 900g of compound II was dissolved in 5L toluene, 368g of potassium tert-butoxide (1.4eq) and 265g (1.3eq) of ethylene carbonate were added in sequence, the reaction solution was stirred for 2h, 3L of water was added, ethyl acetate was extracted, saturated sodium chloride was washed, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (958g, yield 92%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0063] Example 6 Preparation of Compound IV

[0064]

[0065] At 100°C, 1200g of compound II was dissolved in 8L of N,N-dimethylformamide, and 561g of potassium tert-butoxide (1.6eq) and 381g (1.4eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 2h, 6L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethyl acetate-petroleum ether to obtain pure compound IV (1277g, yield 92%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0066] Example 7 Preparation of Compound IV

[0067]

[0068] At 50°C, 1800g of compound II was dissolved in 10L of tetrahydrofuran, and 1215g of potassium carbonate (1.5eq) and 348g (1.2eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 3h, 8L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (1790g, yield 86%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0069] Example 8 Preparation of Compound IV

[0070]

[0071] At 70°C, 800g of compound II was dissolved in 6L of tetrahydrofuran, and 591g of potassium hydroxide (1.8eq) and 290g (1.6eq) of ethylene carbonate were added in sequence. The reaction solution was stirred for 2h, 4L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (2609g, yield 94%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0072] Example 9 Preparation of Compound IV

[0073]

[0074] At 110°C, 800g of compound II was dissolved in 10L of N,N-dimethylformamide, 352g of sodium hydride (1.5eq) and 490g (1.2eq) of ethylene carbonate were added in sequence, the reaction solution was stirred for 1h, 8L of water was added, ethyl acetate was extracted, saturated sodium chloride was washed, concentrated, and recrystallized from ethyl acetate-petroleum ether to obtain pure compound IV (1894g, yield 91%). The NMR and mass spectrometry data were consistent with those in Example 1.

[0075] Example 10 Preparation of Compound Ⅰ

[0076]

[0077] 900 g of compound IV was dissolved in 3 L of 1,2-dichloroethane, 102 g of sodium hydroxide (1.0 eq) was added, the reaction solution was heated to 80 °C and stirred for 2 h, 1.5 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized from ethanol to obtain pure compound I (500 g, yield 90%).

[0078] 1 H-NMR (300MHz, DMSO-d6): δ5.88(d,1H),4.01(m,1H),3.95(m,1H),3.77(m,1H),3.62(m,1H),3 .53(m,1H),3.40(m,1H),2.01(m,1H),1.88(m,1H),1.70(m,2H),1.37(s,3H),1.24(s,3H).EIMS m / z 218.1([M+H] + ).

[0079] Example 11 Preparation of Compound Ⅰ

[0080]

[0081] 2 kg of compound IV was dissolved in 10 L of tetrahydrofuran, 153 g of sodium hydroxide (1.5 eq) was added, the reaction solution was heated to 60 ° C and stirred for 5 h, 5 L of water was added, extracted with dichloromethane, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (1.14 kg, yield 92%).

[0082] The NMR and mass spectrometry data are consistent with those of Example 10.

[0083] Example 12 Preparation of Compound I

[0084]

[0085] 1200 g of compound IV was dissolved in 6 L of N,N-dimethylformamide, 230 g of potassium hydroxide (1.2 eq) was added, the reaction solution was heated to 120 ° C and stirred for 5 h, 3 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (631 g, yield 85%).

[0086] The NMR and mass spectrometry data are consistent with those of Example 10.

[0087] Example 13 Preparation of Compound I

[0088]

[0089] 500 g of compound IV was dissolved in 2.5 L of ethyl acetate, 104 g of potassium hydroxide (1.3 eq) was added, the reaction solution was heated to 70°C and stirred for 4 h, 1.5 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (290 g, yield 94%).

[0090] The NMR and mass spectrometry data are consistent with those of Example 10.

[0091] Example 14 Preparation of Compound I

[0092]

[0093] 800 g of compound IV was dissolved in 4 L of 1,2-dichloroethane, 358 g of potassium tert-butoxide (1.4 eq) was added, the reaction solution was heated to 80 °C and stirred for 4 h, 2 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (440 g, yield 89%).

[0094] The NMR and mass spectrometry data are consistent with those of Example 10.

[0095] Example 15 Preparation of Compound I

[0096]

[0097] 1500g of compound IV was dissolved in 6L of 1,2-dichloroethane, 200g of sodium amide (1.2eq) was added, the reaction solution was heated to 80°C and stirred for 4h, 1L of anhydrous ethanol was slowly added to quench the reaction, 4L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (780g, yield 84%).

[0098] The NMR and mass spectrometry data are consistent with those of Example 10.

[0099] Example 16 Preparation of Compound I

[0100]

[0101] 700 g of compound IV was dissolved in 3 L of N,N-dimethylformamide, 123 g of potassium hydroxide (1.1 eq) was added, the reaction solution was heated to 140 ° C and stirred for 2 h, 2 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (394 g, yield 91%).

[0102] The NMR and mass spectrometry data are consistent with those of Example 10.

[0103] Example 17 Preparation of Compound I

[0104]

[0105] 1400 g of compound IV was dissolved in 7 L of N,N-dimethylformamide, 290 g of potassium hydroxide (1.3 eq) was added, the reaction solution was heated to 160 ° C and stirred for 1 h, 4 L of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and recrystallized with ethanol to obtain pure compound I (806 g, yield 87%).

[0106] The NMR and mass spectrometry data are consistent with those of Example 10.

[0107] The above embodiments are merely examples for clearly illustrating the invention, and are not intended to limit the specific implementation methods of the invention. For those skilled in the art, other modifications or improvements in different forms may be made based on the above description. Obvious modifications or improvements derived therefrom are still within the scope of protection of the claims of the invention.

Claims

1. A method for preparing a key intermediate I of ticagrelor, characterized in that: The following steps are involved: Step a: Compound II reacts with ethylene carbonate in the presence of an organic solvent 1 and a base 1 to obtain compound IV; Step b: Compound IV is hydrolyzed in an organic solvent 2 and a base 2 to obtain compound I; The organic solvent 1 in step a is selected from ethyl acetate, acetonitrile, tetrahydrofuran or dichloromethane; The base 1 in step a is selected from potassium tert-butoxide; The reaction temperature of step a is 0-40°C; The organic solvent 2 in step b is selected from N,N-dimethylformamide or 1,2-dichloroethane; The base 2 in step b is selected from sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium amide; The reaction temperature of step b is 80-160°C.

2. The preparation method according to claim 1, characterized in that The molar ratio of compound II to ethylene carbonate in step a is 1:1.0-1.

2.

3. The preparation method according to claim 1, characterized in that: The reaction time of step a is 3-5h.

4. The preparation method according to claim 1, characterized in that: The molar ratio of compound II to base 1 in step a is 1:1.1-1.

5.

5. The preparation method according to claim 1, characterized in that: The reaction time of step b is 1-5h.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound IV to the base 2 is 1:1.0-1.

4.

7. The preparation method according to claim 1, characterized in that: The step a and step b include a post-treatment step: after extraction with an organic solvent 3, washing with saturated sodium chloride, concentrating, and recrystallizing to obtain a compound; the organic solvent 3 is selected from ethyl acetate or dichloromethane; the recrystallization solvent is selected from ethyl acetate-petroleum ether or ethanol.

8. The preparation method according to claim 1, characterized in that: The step a is to dissolve 2 kg of compound II in 15 L of tetrahydrofuran at 0°C, add 0.8 kg of potassium tert-butoxide and 0.64 kg of ethylene carbonate in sequence, stir the reaction solution for 5 hours, add 10 L of water, extract with ethyl acetate, wash with saturated sodium chloride, concentrate, and recrystallize with ethyl acetate-petroleum ether to obtain pure compound IV; The step b is to dissolve 900g of compound IV in 3L of 1,2-dichloroethane, add 102g of sodium hydroxide, heat the reaction solution to 80°C and stir for 2h, add 1.5L of water, extract with ethyl acetate, wash with saturated sodium chloride, concentrate, and recrystallize with ethanol to obtain pure compound I.

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