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Synthesis method and intermediate compound of nebivolol

A technology of compounds and intermediates, applied in the field of synthesizing nebivolol

Active Publication Date: 2015-05-27
ZHEJIANG AUSUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, although the method of Janssen (Janssen) has a short synthetic route, it needs to separate two diastereoisomeric epoxy intermediates by preparative HPLC, while other methods usually face more synthetic steps and isomeric intermediates. Separation of Constructs

Method used

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  • Synthesis method and intermediate compound of nebivolol
  • Synthesis method and intermediate compound of nebivolol
  • Synthesis method and intermediate compound of nebivolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0355] Example 1: Preparation of 1-benzyloxy-2-bromomethyl-4-fluorobenzene (compound XIV, wherein R is benzyl)

[0356]

[0357] The raw material 2-benzyloxy-5-fluorobenzyl alcohol used in this embodiment can be obtained from the references of known compound 2-hydroxyl-5-fluorobenzyl alcohol (Medicinal Chemistry letters, 2010, vol.1, #7p.321-325 , Bioorganic & Medicinal Chemistry, 2006, vol.14, #6p.2022-2031) method preparation.

[0358] Dissolve 5.14g (22mmol) of 2-benzyloxy-5-fluorobenzyl alcohol in 180mL of anhydrous ether, and drop into PBr at 0°C 3 (2.3mL, 24.4mmol) in 20mL of anhydrous diethyl ether solution was raised to room temperature for 2h, and TLC showed that the reaction was complete.

[0359] Post-processing: add 50mL of water, separate the organic layer, extract the aqueous layer with (50mL*3) DCM, combine the organic phase, wash with saturated sodium bicarbonate, wash with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filte...

Embodiment 2

[0361] Example 2: Preparation of 4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane (compound XV, wherein R is benzyl)

[0362]

[0363] Add 2.4mL, 16.1mmol trimethylsilylpropyne to 40mL anhydrous THF, cool to -23°C, add 2.5M n-BuLi 7.7mL (19.3mmol) dropwise, and stir at this temperature for 2h until the reaction liquid After cooling down to -100°C, 3.5g (11.9mmol) of compound XIV (wherein R is benzyl) in 5mL of anhydrous THF solution was added dropwise, and the reaction was completed at this temperature for 1h, and TLC showed that it was complete.

[0364] Post-processing: stop the reaction with 10% saturated ammonium chloride, separate several layers, extract the aqueous layer (100mL*2) with ether, combine the organic phases, wash with saturated ammonium chloride, dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography (PE / Et 2 O=100:1) to obtain 3.79 g of pure product with a yield of 97.6%.

[0365] 1 H-NMR (400MHz, CDCl 3 )δ7.38~7.4...

Embodiment 3

[0366] Example 3: Preparation of 1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene (compound XVI, wherein R is benzyl)

[0367]

[0368] Dissolve 1.15g (3.52mmol) of compound XV (wherein R is benzyl) in 20ml of MeOH, add 0.5g (3.6mmol) of K 2 CO 3 , stirred at room temperature for 3h, the solvent was evaporated under reduced pressure, the residue was extracted with EtOAc, washed with water, washed with saturated NaCl, anhydrous NaCl 2 SO 4 , dried, filtered, and the filtrate was evaporated to dryness to obtain 0.87 g of a colorless oil. Filter through a short column of silica gel and elute with PL / EtOAc (100 / 2) to obtain 0.85 g of a colorless oil.

[0369] 1 H-NMR (400MHz, CDCl 3 )δ7.33~7.42(m, 5H), 6.93~6.96(dd, J=9.6, 2.8Hz, 1H), 6.81~6.86(m, 2H), 5.05(s, 2H), 2.86~2.90(t, J=7.2Hz, 2H), 2.47~2.51(t, J=7.2Hz, 2H), 1.96(s, 1H)

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Abstract

The present invention relates to a synthesis method and an intermediate compound of nebivolol. Specifically the invention relates to the method for synthesizing the nebivolol, the intermediate compound of the nebivolol, and a method for preparing the intermediate compound.

Description

technical field [0001] The present invention relates to the synthetic method of medicine and its intermediate compound, specifically, relate to the method for synthesizing nebivolol, its intermediate compound and the method for preparing said intermediate compound. Background technique [0002] Nebivolol hydrochloride, the chemical name is (+ / -)-bis[2-(6-fluorochroman-2-yl)-2-hydroxyethyl]amine (formula I) hydrochloride, It is a highly selective third-generation beta-blocker developed by Johnson Company with vasodilator effect, mainly used for the treatment of mild to moderate hypertension, angina pectoris and congestive heart failure. Clinically applied nebivolol hydrochloride is a mixture of equal amounts of the dextro isomer (structural formula Ia) and the levoisomer (structural formula Ib), that is, its racemate (formula I). The β receptor blocking effect of nebivolol hydrochloride mainly comes from the dextro isomer, but other effects depend on the co-existence of the ...

Claims

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Application Information

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IPC IPC(8): C07D311/58C07D303/22C07D301/14C07D301/19C07F7/08C07C41/22C07C43/225C07C41/18C07C41/30C07C43/23C07C41/20
CPCY02P20/55
Inventor 郑志国
Owner ZHEJIANG AUSUN PHARMA
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