US 9,809,585 B2
Fluorinated 2-arylbenzo heterocyclic compound with high affinity to Aβ 946; plaques and containing chiral side chain substituent, and preparation method and usage thereof
Mengchao Cui, Beijing (CN); Chunping Lin, Beijing (CN); Boli Liu, Beijing (CN); Yuzhi Guo, Beijing (CN); and Zhiyong Zhang, Beijing (CN)
Assigned to BEIJING ZHIBO BIO-MEDICAL TECHNOLOGY CO., LTD, Beijing (CN); and Zhiyong Zhang, Beijing (CN)
Appl. No. 14/890,922
Filed by BEIJING ZHIBO BIO-MEDICAL TECHNOLOGY CO.,LTD, Beijing (CN)
PCT Filed Nov. 7, 2014, PCT No. PCT/CN2014/090536
§ 371(c)(1), (2) Date Nov. 13, 2015,
PCT Pub. No. WO2015/184731, PCT Pub. Date Dec. 10, 2015.
Claims priority of application No. 2014 1 0247965 (CN), filed on Jun. 6, 2014.
Prior Publication US 2016/0207910 A1, Jul. 21, 2016
Int. Cl. C07D 417/04 (2006.01); C07D 413/04 (2006.01); C07D 263/57 (2006.01); C07D 277/66 (2006.01); A61K 51/04 (2006.01); A61K 49/10 (2006.01)
CPC C07D 417/04 (2013.01) [A61K 49/10 (2013.01); A61K 51/0453 (2013.01); A61K 51/0455 (2013.01); C07D 263/57 (2013.01); C07D 277/66 (2013.01); C07D 413/04 (2013.01)] 1 Claim
 
1. A preparation method of a compound shown as Formula (I):

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wherein X is N; Y is S; Z is N; R1 is

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F in R1 is 18F; and R2 is N(CH3)2,
wherein the preparation method of the compound consists of steps of:
(1) dissolving 1 mmol of

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in 30 mL of anhydrous ethanol and adding 0.3 mL of a 200 g/L NaOH solution to a mixture thereof, wherein X is N; Y is S; Z is N; R is N(CH3)2; stirring the mixture in an oil bath at 80° C. until reflux lasts for 1 h; adding 1.5 mmol of

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to the mixture; after reaction is completed, removing a solvent; wherein after column chromatography separation, a compound with a Formula (VI) shown below is obtained:

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(2) when R is NHCH3, dissolving 1 mmol of the compound with the Formula (VI), 8 mmol of imidazole and 8 mmol of tert-butyldimethylsilyl chloride in 30 mL of a CH2Cl2 solution; stirring a mixture thereof in an oil bath at 40° C. until reflux lasts for 5 h; after reaction is completed, removing CH2Cl2; wherein after the column chromatography separation, a compound with a Formula (VIII) shown below is obtained:

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(3) dissolving 1 mmol of the compound with the Formula (VIII) in 30 mL of a THF solution and adding an excessive dose of (Boc)2O (Di-tert-butyl decarbonate) to a mixture thereof; stirring the mixture in an oil bath at 80° C. until reflux lasts for a night; after reaction is completed, removing the THF; wherein after the column chromatography separation, a compound with a Formula (XI) shown below is obtained:

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(4) dissolving 1 mmol of the compound with the Formula (XI) in 30 mL of the THF solution and adding 7 mmol of TBAF to a mixture thereof; stirring the mixture in an oil bath at 30° C. until reflux lasts for one night; after reaction is completed, removing the THF; wherein after the column chromatography separation, a compound with a Formula (XII) shown below is obtained:

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(5) dissolving 1 mmol of the compound with the Formula (VI) and 1 mmol of the compound with the Formula (XII) in 5 mL of pyridine respectively and adding 1.5 mmol of TsCl to a mixture thereof; stirring the mixture in an ice bath at 0° C. until reactions occur; after the reactions are completed, removing the pyridine; wherein after the column chromatography separation, a compound with a Formula (XV) shown below is obtained:

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wherein X is N; Y is S; Z is N; R is N(CH3)2;
(6) dissolving 1 mmol of the compound with the Formula (XV), 4 mmol of 3,4-dihydro-2H-pyran and 0.2 mmol of PPTS (Pyridinium p-toluenesulfonate) in 30 mL of a CH2Cl2 solution respectively; stirring a mixture thereof in an oil bath at 40° C. until reflux lasts for a night; after reaction is completed, removing CH2Cl2; wherein after the column chromatography separation, a compound with a Formula (XVII) shown below is obtained:

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and
(7) dissolving 10 mg of the compound with the Formula (XVII) in 2 mL of acetonitrile; adding a mixture thereof to a reaction tube of dehydrated 18F and K222/K2CO3; maintaining labeling at 100° C. for 12 min; after the mixture is cooled, adding 0.15 mL of 1M HCl; after swirling is completed, keeping reacting for 5 min; after the mixture is cooled, adding a small amount of water and neutralizing the mixture with NaHCO3 until the mixture is alkaline; separating the mixture with a C18 reverse phase column and rinsing the mixture with water to remove salts and residual 18F; then rinsing the mixture with the acetonitrile; after the mixture is dried with N2, separating with HPLC to obtain a compound with a Formula (XIV) shown below:

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