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Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method

A technology of ticagrelor and racemate, which is applied in the new synthesis field of key intermediates of ticagrelor, can solve the problems of high cost of camphorsulfonamide, poor ring-closing selectivity, and low total yield, and achieves The effect of simple and convenient post-processing, environmental friendliness, safe and easy operation

Active Publication Date: 2014-01-15
KAIYUAN HENGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Route 3: WO2011 / 01718 reported the synthesis of this compound. This route uses 3,4-difluorobenzaldehyde as a raw material to obtain compound VII after 6 steps of reaction. However, the cost of camphorsulfonamide in this route is relatively high, and the ring-closing The selectivity is not good, the disadvantage of using sodium azide and the overall yield of the route is not high

Method used

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  • Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method
  • Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method
  • Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070]

[0071] At an internal temperature lower than 30°C, 1,2-difluorobenzene (20g, 0.175mol, 1eq) and A mixture of 3-chloropropionyl chloride (24.30g, 0.193mol, 1.1eq). Keep the temperature of the reaction system below 30°C. After the dropwise addition, the reaction was stirred overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was slowly poured into ice water, the organic phase was separated, washed with water, dried and concentrated to obtain the crude yellow liquid compound I. No purification is required. Yield: 31.5 g, yield: 88%.

[0072] 1 HNMR (400MHz, DMSO- d 6 ): δ7.829-7.728(m, 2H), 7.294-7.249(m, 1H), 3.913(t, J =6.8 Hz, 2H), 3.419(t, J =6.8 Hz, 2H).

Embodiment 2

[0074]

[0075] 1) Under stirring at room temperature, trimethyl borate (1.67g) was added to a mixture of L-diphenylprolinol (2.9g) in toluene (75mL). After the mixture was stirred at 40°C for 1 hour, borane dimethyl sulfide (10mol / L, 13.9g) was added dropwise, and the temperature was controlled not to be higher than 45°C. The mixture was stirred at 40°C for 1 hour.

[0076] 2) Slowly add a solution of 3-chloro-1-(3,4-difluorophenyl)propyl-1-one (compound I, 46.8g) in toluene (110mL) to the above mixture, and control the temperature at 35°C-40°C. After the dropwise addition, the reaction system was stirred at 40° C. for 1 hour. TLC (PE / EA, 3 / 1, V / V) followed the completion of the reaction. The temperature of the reaction system was lowered to 10°C, methanol (40 mL) was slowly added to quench the reaction, the temperature was controlled below 35°C, and stirred for 30 minutes. The mixture was concentrated to about 100 mL under reduced pressure, and washed three times with...

Embodiment 3

[0079]

[0080] Compound II (6.2 g, 3 mmol, 1 eq) was dissolved in dimethyl sulfoxide (20 mL) at room temperature. Sodium cyanide (2.14g, 4.5mol, 1.5eq) was added carefully. The reaction was stirred overnight at 60 °C. After TLC showed that there was no raw material, cool, add 50 mL of water, extract with ethyl acetate (100 mL), concentrate the organic phase, add 50 mL of water to the residue, extract with ethyl acetate (100 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate. The crude product of compound III (6.3 g) was obtained, which was directly put into the next reaction.

[0081] 1 HNMR (400MHz, DMSO- d 6 ): δ1.795-1.834(m, 1H), 1.892-1.924(m, 1H), 2.487-2.533(m, 2H), 4.586-4.631(m, 1H), 5.679(d, J =4.4 Hz, 1H), 7.174-7.206(m, 1H),7.355-7.423(m, 2H).

[0082] 13 CNMR (100MHz, DMSO- d 6 ): δ12.986, 34.037, 69.495, 114.664(d, J =17 Hz), 117.088(d, J =17 Hz), 120.416, 122.322, 142.688, 147.655(dd, J 1 =86.6Hz, J 2 =12.5 Hz), 150.085(...

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Abstract

The invention discloses a method for preparing a ticagrelor key intermediate VII and a racemate thereof. The method comprises the following steps: by using a compound V or a racemate thereof as a raw material, performing acidic hydrolysis to obtain a compound VI or a racemate thereof; and performing Curtis rearrangement to obtain a compound VII or a racemate thereof. According to the ticagrelor key intermediate and the racemate thereof prepared by the method, the adopted initial raw materials are low in price and readily available, the requirements of reaction conditions on solvents are low, the operation is safe, simple and convenient, and the method is environment-friendly; moreover, when the ticagrelor key intermediate and the racemate thereof are prepared by adopting a special intermediate, the after-treatment is simple and convenient, and the large-scale production is more easily realized.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis. Specifically, it is a new synthesis method for the key intermediate of ticagrelor for reducing cardiovascular death and heart attack in patients with acute coronary syndrome (ACS). technical background [0002] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells (VSMC), does not require metabolic activation, and has a significant effect on platelet aggregation induced by adenosine diphosphate (ADP). Inhibitory effect, and rapid onset after oral administration, can effectively improve the symptoms of patients with acute coronary heart disease. Unlike thienopyridines, ticagrelor is a reversible inhibitor of P2Y12 receptors, so it is especially suitable for patients who need anticoagulant therapy before surgery. [0003] (1...

Claims

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Application Information

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IPC IPC(8): C07C211/40C07C209/56C07C255/35C07C255/46C07C253/30
Inventor 陈平彭少平蔡振伟安荣昌
Owner KAIYUAN HENGTAI PHARMA
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