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Synthesis method of AV-45 intermediate

A synthesis method and tert-butyl technology are applied in the preparation of amino compounds from amines, organic chemistry, etc., can solve problems such as low yield, long reaction route, inconvenient post-processing, etc., and achieve high yield, low cost, and easy operation. easy effect

Active Publication Date: 2020-08-07
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The object of the present invention is to disclose a kind of synthetic method of the AV-105 of structure shown in formula (I), in order to overcome the long reaction route in existing synthetic route, yield is low, use has irritating smell reagent and post-processing inconvenient and other problems, the intermediates and target compounds prepared by this route can be directly purified by recrystallization. This method is easy to operate, suitable for scale-up production, and has the advantage of high yield

Method used

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  • Synthesis method of AV-45 intermediate
  • Synthesis method of AV-45 intermediate
  • Synthesis method of AV-45 intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Under nitrogen protection, tert-butyl-N-methyl-4-vinylphenylcarbamate (5.13g, 22mmol), 2-bromo-5-iodopyridine (5.66g, 20mmol), TBAB (12.9 g, 40mmol), K 2 CO 3 (6.91g, 50mmol), Pd(OAc) 2 (224mg, 1.0mmol) was suspended in 150mL DMF and reacted at 65°C for 3 hours. Cool down to room temperature, add 300 mL of water, and extract with ethyl acetate (300 mL×3). The organic phases were combined and washed with saturated brine (500 mL×2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from dichloromethane / n-hexane to obtain 6.43 g of white solid, with a yield of 82.6%.

Embodiment 2

[0050] Under nitrogen protection, tert-butyl-N-methyl-4-vinylphenylcarbamate (5.13g, 22mmol), 2-bromo-5-iodopyridine (5.68g, 20mmol), PdCl 2 (177mg, 1.0mmol), TBAB (645mg, 2mmol), K 2 CO 3 (2.76g, 20mmol) was suspended in 100mL DMF and reacted at 65°C for 3 hours. Cool down to room temperature, add 200 mL of water, and extract with ethyl acetate (200 mL×3). The organic phases were combined and washed with saturated brine (500 mL×2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from acetonitrile to obtain 6.03 g of a white solid with a yield of 77.4%.

Embodiment 3

[0052] Under nitrogen protection, tert-butyl-N-methyl-4-vinylphenylcarbamate (5.13g, 22mmol), 2-bromo-5-iodopyridine (5.68g, 20mmol), Pd(OAc ) 2 (224mg, 1.0mmol), TBAB (645mg, 2mmol), K 2 CO 3 (2.76g, 20mmol) was suspended in 100mL DMF and reacted at 65°C for 3 hours. Cool down to room temperature, add 200 mL of water, and extract with ethyl acetate (200 mL×3). The organic phases were combined and washed with saturated brine (500 mL×2). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was recrystallized from acetonitrile to obtain 5.87 g of a white solid with a yield of 75.4%.

[0053] Step (2): Intermediate A is condensed with triethylene glycol to obtain a compound of formula (I)

[0054]

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Abstract

The invention provides a synthesis method of an AV-45 intermediate. The synthesis method comprises the following steps: (1) carrying out an HECK reaction on tert-butyl-N-methyl-4-vinylphenyl carbamateand 2-bromo-5-iodopyridine to obtain an intermediate A; and (2) condensing the intermediate A and triethylene glycol to obtain a target compound, namely the AV-45 intermediate. According to the invention, a conventional synthesis method of (E)-tert-butyl-4-(2-(6-(2-(2-(2-hydroxyethyl)ethoxy)ethoxy)pyridin-3-yl)vinyl)phenyl(methyl)carbamate is improved; few reaction steps are included, and the useof reagents with pungent smell is avoided; and of the intermediate and the target compound prepared through the method can be direct purified through recrystallization, operation is simple, and yieldis high.

Description

technical field [0001] The present invention relates to the field of pharmaceutical synthesis, in particular to an AV-45 intermediate (i.e. (E)-tert-butyl-4-(2-(6-(2-(2-(2-hydroxyethoxy)ethoxy) base) ethoxy) pyridin-3-yl) vinyl) phenyl (methyl) carbamate) synthetic method. Background technique [0002] 18 F-AV-45 (florbetapir), developed by Avid Company of the United States, was the first positron imaging agent approved by the Food and Drug Administration (FDA) of the United States in 2012 for the diagnosis of AD. The imaging agent achieves the purpose of diagnosis by specifically binding to Aβ, and realizes the observation of Aβ deposition changes in vivo in a non-invasive way. It has been widely used in clinical research on Aβ-related diseases. (E)-tert-butyl-4-(2-(6-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)phenyl ( Methyl) carbamate is a synthetic 18 The intermediate of F-AV-45 can be obtained from this compound through sulfonate esterification, fluorin...

Claims

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Application Information

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IPC IPC(8): C07D213/64C07C209/68C07C211/48
CPCC07D213/64C07C209/68C07C211/48Y02P20/55
Inventor 李祎亮段玉清贾建华于江宁洪鑫毕常芬魏会强樊赛军
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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