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Cangrelor intermediate and preparation method and application thereof

A technology of reaction and reaction solvent, applied in the field of cangrelor preparation, can solve problems such as difficulty in product purification, and achieve the effects of easy operation, high purity and good stability

Active Publication Date: 2016-01-27
SHANGHAI INST OF PHARMA IND CO LTD +2
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AI Technical Summary

Problems solved by technology

The production of this by-product makes product purification difficult and is gradually carried into subsequent products

Method used

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  • Cangrelor intermediate and preparation method and application thereof
  • Cangrelor intermediate and preparation method and application thereof
  • Cangrelor intermediate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-4

[0033] Example 1-4: Synthesis of 2-[(3,3,3-trifluoropropyl)thio]adenosine-2',3',5'-triethyl ester (2)

[0034] 2-[(3,3,3-trifluoropropyl)thio]adenosine (10.0g, 25.3mmol) was dissolved in pyridine (20ml, 253mmol, 10eq), and acetic anhydride (35ml, 5eq), reacted at -5°C for 3h, added 100ml of water to precipitate a white solid, stirred for 1h and filtered with suction to obtain 11.35g of a white solid, with a yield of 86%. ESI-MS(m / z): 522.13[M+H] + , 544.11[M+Na] + , 560.09[M+K] + ; 1HNMRδ (CDCl 3 ) 7.87 (1H, s, H-8), 6.14 (1H, d, H-1'), 5.82 (1H, t, H-2'), 5.67 (2H, s, NH 2 ), 5.45 (1H, m, H-3'), 4.41 (3H, m, H-4', 5'), 3.29 (2H, m, SCH 2 ),2.63(2H,m,CF 3 CH 2 ), 2.13 (3H, s, CH 3 CO), 2.12 (3H, s, CH 3 CO), 2.07 (3H, s, CH 3 CO).

[0035] Dissolve 2-[(3,3,3-trifluoropropyl)thio]adenosine (5.0g, 12.65mmol) in acetic anhydride (60ml, 632.34mmol, 50eq) to -15°C, add triethyl Amine (3.84g, 3eq), reacted for 7h, added 50ml of water to precipitate a white solid, stirred...

Embodiment 5-8

[0038] Example 5-8 Synthesis of N-formyl-2-[(3,3,3-trifluoropropyl)thio]adenosine-2',3',5'-triacetyl (3)

[0039] Formic acid (13ml, 345mmol, 18eq) was added to acetic anhydride (27ml, 288mmol, 15eq) at low temperature, stirred at 50°C for 30min, cooled to room temperature, compound 2 (10.0g, 19.2mmol) was added, and reacted at 70°C for 3.5h. Add 65ml of water to precipitate a white solid, stir at about 20°C for 2h and filter with suction to obtain compound (3) (9.86g, yield 94.0%). ESI-MS (m / z): 572.15[M+Na] + ; 1HNMRδ (CDCl 3 ) 9.83 (2H, s, NH+CHO), 8.40 (1H, s, H-8), 6.21 (1H, d, H-1'), 5.85 (1H, t, H-2'), 5.56 (1H , t, H-3'), 4.40(3H, 4-H'+5-2H'), 3.32(2H, SCH 2 ), 2.64 (2H, CF 3 -CH 2 ), 2.15-2.07 (6H, CH 3 CO).

[0040] Formic acid (14.47ml, 383.5mmol, 50eq) was added to acetic anhydride (7.25ml, 76.7mmol, 10eq) at low temperature and stirred at 50°C for 30min, lowered to 25°C, compound 2 (4.0g, 7.67mmol) was added, and reacted at 60°C 10h. Add 65ml of water to ...

Embodiment 9-12

[0043] Example 9-12: N-formyl-N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]adenosine-2',3 Synthesis of ',5'-triacetyl(4)

[0044] Dissolve compound 3 (8.0g, 14.6mmol) in 80ml of DMF, then add potassium carbonate (4.02g, 2eq), react at 60°C for 1h, add 2-chloroethyl methyl sulfide (4.35ml, 3eq) and react at 60°C After 2 hours, 8.58 g of dark syrup was obtained, with a yield of 94%. TLC (dichloromethane: methanol = 20:1) R f = 0.9.

[0045] Dissolve compound 3 (5.0g, 9.1mmol) in 50ml of DMF, then add triethylamine (1.3ml, 1eq), react at 60°C for 1h, add 2-chloroethyl methyl sulfide (1.81ml, 2eq) at 25°C After 15 hours of reaction, 3.42 g of dark syrup was obtained, with a yield of 60%.

[0046] Dissolve compound 3 (4.0g, 7.3mmol) in 40ml DMF, add sodium carbonate (1.54g, 2eq), react at 60°C for 1h, add 2-chloroethyl methyl sulfide (2.2ml, 3eq) and react at 60°C After 2 hours, 4.34 g of dark syrup was obtained, with a yield of 95%.

[0047] Dissolve compound 3 (4....

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Abstract

The invention relates to the technical field of preparation method of cangrelor. The invention discloses a new intermediate compound 3 for preparing cangrelor. The invention discloses the new intermediate compound 3 for preparing cangrelor and a preparation method thereof. By changing an N- protection group, and adopting weaker-activity formyl as an N protection group, the new N-formyl protective intermediate 3 is obtained successfully; the intermediate has the advantages of high purity, good stability, easy operation of preparation method and the like. The difficulties in the prior art that the yield is low and the product is difficult to purify and separate are solved.

Description

technical field [0001] The invention relates to the technical field of cangrelor preparation methods. Background technique [0002] Cangrelor, English name: cangrelor, chemical name: N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenosine Acid, monoanhydride with dichloromethylene diphosphoric acid, tetrasodium salt, chemical structure: [0003] [0004] Cangrelor is developed by The Medicines Company, a pharmaceutical company, and is currently in Phase III clinical trials. It belongs to platelet ADP (P 2 Y 12 ) receptor antagonist antiplatelet drugs. [0005] Regarding the synthesis of cangrelor, there are special descriptions in the patent CN1042430C and the paper J.Med.Chem.1999, 42, 213-220, all of which use N-acetyl-2-[(3, 3,3-trifluoropropyl)thio]adenosine-2',3',5'-triethyl ester (compound of the following formula 6) as a key intermediate in the synthetic route. Taking J.Med.Chem.1999, 42, 213-220 as an example, 2-[(3,3,3-trifluoropropyl)thio]adeno...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167C07H19/20C07H1/00
Inventor 王庆荣王胡博朱雪焱袁哲东
Owner SHANGHAI INST OF PHARMA IND CO LTD
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