Process for the preparation of ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine

Abstract

The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of a ticagrelor intermediate (1R, 2S)-2-(3, 4-difluorophenyl)cyclopropylamine, which comprises the following steps: taking compound II as raw material, and reacting with N-bromosuccinimide and sodium acetate to prepare target intermediate compound I. Compared with the prior art, the reaction has the advantages of mild reaction condition, simple operation, high safety, simple post-treatment, and safety and environmental protection. It is determined that the yield of the product prepared by the technical scheme disclosed in the application can reach more than 88%, and the purity is more than 99%.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, particularly the field of pharmaceutical preparation, and more specifically, to a method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine. Background Technology

[0002] Ticagrelor (also known as ticagrelor) is a novel, selective small-molecule anticoagulant developed by AstraZeneca. It is the first reversible, oral conjugated P2Y12 adenosine diphosphate receptor antagonist, significantly inhibiting ADP-induced platelet aggregation and effectively improving symptoms in patients with acute coronary heart disease. The drug was approved for marketing in the European Union and the United States in 2010 and 2011 by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA), respectively. Its imported formulation, ticagrelor tablets, has been approved for marketing in my country by the SFDA.

[0003] Compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I) is a key intermediate in the synthesis of ticagrelor.

[0004] Patent CN102796007 reports a synthetic route for preparing 3,4-difluorocinnamate from 3,4-difluorobenzaldehyde via reaction with phosphorus ylide reagent; followed by Simons-Smith asymmetric cyclopropanation with diiodomethane in the presence of chiral ligands and diethylzinc to yield trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate, which is then subjected to ammonolysis and Hoffmann rearrangement to obtain the target compound. The synthetic route is as follows:

[0005]

[0006] Patent CN104311432A reports another preparation route, which prepares (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine via cyclopropanation, hydrolysis, and Hoffman degradation. The synthetic route is shown below:

[0007]

[0008] It is evident that the commonly used method in current technologies is to convert compound II into compound I, the target compound, through the Hoffmann degradation reaction. The synthetic route can be represented as follows:

[0009]

[0010] The inventors of this invention have discovered that although compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I) is an important intermediate compound in the synthesis of ticagrelor, and its synthesis methods have been extensively studied in the prior art, the chiral target compound I is usually obtained by the Hoffmann rearrangement reaction of compound II.

[0011] The Hoffmann rearrangement reaction involves numerous side reactions, such as the hydrolysis of the amide to form a carboxylic acid and the excessive oxidation of the amide to form an acylurea. This increases the difficulty of separating and purifying the target product. Furthermore, the reaction requires sodium hypochlorite, which necessitates the use of chlorine gas, a gas with high transportation costs. The reaction also generates a large amount of solid waste; one molecule of sodium hypochlorite produces at least two molecules of sodium chloride. The environmental treatment costs of this sodium chloride waste further increase the company's production costs, thus impacting the production cost of ticagrelor. Summary of the Invention

[0012] This invention addresses the problems of numerous byproducts, poor production safety, and environmental pollution associated with the preparation of Compound I in existing technologies. It discloses a method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (Compound I), aiming to overcome these problems and obtain a safe and environmentally friendly production method. Furthermore, another objective of this invention is to further improve the yield and purity of the target product, meeting the needs of modern large-scale industrial production.

[0013] To achieve the above-mentioned objective, this invention discloses a method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine. The method involves reacting compound II with N-bromosuccinimide and sodium acetate in the presence of a solvent at 20–100 °C to obtain (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I).

[0014]

[0015] Furthermore, the preparation method of the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine is as follows: under an argon atmosphere, compound II is mixed with a solvent, and then N-bromosuccinimide and sodium acetate are added. The mixture is stirred continuously at 20-100°C to obtain a product containing (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I).

[0016] Preferably, the molar ratio of compound II to N-bromosuccinimide is 1:1 to 2, more preferably 1:1.5.

[0017] Preferably, the molar ratio of compound II to sodium acetate is 1:1 to 2, more preferably 1:1.4.

[0018] Furthermore, the solvent is selected from one or more of dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or acetone.

[0019] Furthermore, the reaction temperature is preferably 30℃ to 80℃, including but not limited to 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃ or 80℃. To obtain better results, the reaction temperature is preferably 50℃.

[0020] Furthermore, the reaction time is 3 to 12 hours, including but not limited to 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours. To obtain better results, the reaction time is preferably 6 hours.

[0021] Furthermore, it also includes a post-processing step for the product, specifically, first removing the reaction solvent, then adding ethyl acetate and water for extraction, washing the extract with saturated brine, taking the organic solvent layer, drying, concentrating under reduced pressure, and distilling to obtain purified (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I).

[0022] This invention discloses a method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine. The method uses compound II as a starting material, reacting it with N-bromosuccinimide and sodium acetate to prepare the target intermediate compound I. Compared to existing technologies, this reaction produces fewer byproducts, eliminates the need for high-waste-generating raw materials such as sodium hypochlorite, employs mild reaction conditions, is simple to operate, and is highly safe. Furthermore, it requires only simple post-processing to obtain the target compound with high purity (over 99%) and a high synthesis yield. Detailed Implementation

[0023] To better understand the present invention, we will further elaborate on the present invention below with reference to specific embodiments.

[0024] Unless otherwise specified, all reagents used in the embodiments of this invention are commercially available products.

[0025] Example 1

[0026] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 95.7% yield and with a purity of 99.3%.

[0027] Example 2

[0028] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethyl sulfoxide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 20 °C for 12 h. After the reaction was complete, the dimethyl sulfoxide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 93.2% yield and with a purity of 99.1%.

[0029] Example 3

[0030] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethyl sulfoxide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 100 °C for 3 h. After the reaction was complete, the dimethyl sulfoxide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 92.6% yield and with a purity of 99.2%.

[0031] Example 4

[0032] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of tetrahydrofuran were added to a reactor, followed by N-bromosuccinimide (18 g, 101.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the tetrahydrofuran was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 94.4% yield and 99.3% purity.

[0033] Example 5

[0034] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of tetrahydrofuran were added to a reactor, followed by N-bromosuccinimide (9.1 g, 51 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the tetrahydrofuran was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 88.2% yield and with a purity of 99.1%.

[0035] Example 6

[0036] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of acetone were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (8.3 g, 101.2 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the acetone was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 93.8% yield and with a purity of 99.4%.

[0037] Example 7

[0038] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of acetone were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (4.2 g, 51 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the acetone was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 89.3% yield and with a purity of 99.2%.

[0039] Comparative Example 1

[0040] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 10 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 66.3% yield with a purity of 95.7%.

[0041] Comparative Example 2

[0042] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 110 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 71.6% yield with a purity of 97.2%.

[0043] Comparative Example 3

[0044] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 2 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 68.4% yield with a purity of 95.9%.

[0045] Comparative Example 4

[0046] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 13 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 75.1% yield and 96.3% purity.

[0047] Comparative Example 5

[0048] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (8.2 g, 46 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 65.9% yield and 95.3% purity.

[0049] Comparative Example 6

[0050] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (18.9 g, 106 mmol) and sodium acetate (5.8 g, 71 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 81.7% yield with a purity of 98.2%.

[0051] Comparative Example 7

[0052] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (3.8 g, 46 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 69.4% yield and with a purity of 96.1%.

[0053] Comparative Example 8

[0054] Under an argon atmosphere, compound II (10 g, 50.7 mmol) and 100 mL of dimethylformamide were added to a reactor, followed by N-bromosuccinimide (13.5 g, 76.1 mmol) and sodium acetate (8.7 g, 106 mmol). The reaction mixture was stirred at 50 °C for 6 h. After the reaction was complete, the dimethylformamide was distilled off, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with 100 mL of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and compound I was obtained by distillation in 83.2% yield and with a purity of 97.5%.

[0055] The above describes specific embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine, characterized in that: The preparation method involves reacting compound II with N-bromosuccinimide and sodium acetate at 30-80°C in the presence of a solvent to obtain (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I); the solvent is selected from one or more of dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or acetone. ； The reaction time is 3-12 hours; The molar ratio of compound II to N-bromosuccinimide is 1:1.5~2; The molar ratio of compound II to sodium acetate is 1:1.4~2.

2. The method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine according to claim 1, characterized in that, The preparation method is as follows: under an argon atmosphere, compound II is mixed with a solvent, and then N-bromosuccinimide and sodium acetate are added. The mixture is stirred continuously at 30~80℃ to obtain a product containing (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I).

3. The method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine according to claim 1, characterized in that, The reaction temperature is 50℃.

4. The method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine according to claim 1, characterized in that, The reaction time is 6 hours.

5. The method for preparing the ticagrelor intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine according to claim 1 or 2, characterized in that, It also includes a post-processing step for the product, specifically, removing the reaction solvent first, then adding ethyl acetate and water for extraction, washing the extract with saturated brine, taking the organic solvent layer, drying, concentrating under reduced pressure, and distilling to obtain purified (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound I).

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