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A compound and molar ratio technology, applied in the field of drug synthesis, can solve the problems of non-recyclability, serious and highly toxic oxazaborolane environmental pollution, etc.
Inactive Publication Date: 2013-12-11
NANJING UNIV OF TECH
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[0019] The main disadvantage of this synthetic method utilizing chiral oxazoborane catalytic reduction is that the highly toxic oxazolidine has serious environmental pollution and cannot be reused.
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Embodiment 1
[0037] Example 1: 4-Hydroxy-3-Hydroxymethylbenzaldehyde 2 Synthesis
[0038] 12.20 g (0.10 mol) of p-hydroxybenzaldehyde, 40% hydrochloric acid (88 mL), and 6 g (0.20 mol) of paraformaldehyde were successively added to a 250 mL four-necked flask, and stirred at 60° C. for 3 h. Cool to room temperature, filter to obtain a white solid, wash with water (300mL×3), filter with suction, dry to obtain a white solid, wash with an appropriate amount of methanol to obtain a white solid compound 2 , yield 63%, melting point 142-143 °C, 1 H-NMR: (400MHz, DMSO-d 6 )δ9.81(s, 1H, CHO), 7.89(s, 1H, Ar-H), 7.65(d, J=8.0Hz, 1H, Ar-H), 6.94(d, J=8.0Hz, 1H, Ar-H) 5.17(s, 1H, OH), 4.51(s, 2H, CH 2 ).
Embodiment 2
[0039] Example 2: 4-Hydroxy-3-Hydroxymethylbenzaldehyde 2 Synthesis
[0040] Add 12.20g (0.10mol) of p-hydroxybenzaldehyde, dilute sulfuric acid (100mL) with a mass fraction of 20%, and 6g (0.20mol) of paraformaldehyde into a 250mL four-necked flask in sequence, stir at 50°C and pass in hydrogen chloride gas 4h. Cool to room temperature, filter to obtain a white solid, wash with water (300mL×3), filter with suction, dry to obtain a white solid, wash with an appropriate amount of methanol to obtain a white solid compound 2 , yield 51%.
Embodiment 3
[0041] Example 3: 4-Hydroxy-3-Hydroxymethylbenzaldehyde 2 Synthesis
[0042] Add 12.20 g (0.10 mol) of p-hydroxybenzaldehyde, boric acid (80 mL), and 6 g (0.20 mol) of paraformaldehyde into a 250 mL four-necked flask in sequence, stir at 65° C. and pass in hydrogen chloride gas for 2 h. Cool to room temperature, filter to obtain a white solid, wash with water (300mL×3), filter with suction, dry to obtain a white solid, wash with an appropriate amount of methanol to obtain a white solid compound 2 , yield 63%.
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Abstract
The invention discloses a method for synthesizing (R)-salmeterol. The method is implemented by taking p-hydroxy benzaldehyde as a raw material through the steps of carrying out a methylolation reaction on the p-hydroxy benzaldehyde so as to obtain prochiral aldehyde for protecting double hydroxide radicals in an acetal form; then, through taking (S)-BINOLAM.AlCl as a chiral catalyst, carrying out an asymmetric nucleophilic addition reaction so as to obtain a chiral cyanohydrin intermediate; and reducing the chiral cyanohydrin intermediate so as to obtain primary amine, reacting the primary amine with mesylate [6-(4 phenylbutoxy]hexane, and carrying out hydrolysis on the obtain product so as to remove protecting groups, thereby obtaining a final product (R)-salmeterol. In the invention, a chiral catalyst precursor (S)-BINOLAM can be reused; and the method has relatively high yield and relatively good enantioselectivity, and is short in synthetic route, simple and convenient in operation and low in cost.
Description
technical field [0001] The invention belongs to the field of medicine synthesis. It specifically relates to a method for synthesizing selective β2-adrenal receptor agonist (R)-salmeterol. technical background [0002] The present invention relates to the synthesis of (R)-salmeterol which has anti-inflammatory activity and long-acting selective β2-adrenal receptor agonist. It has the following structural features: [0003] [0004] Bronchial asthma is a kind of common disease, frequently-occurring disease, is the important disease that affects people's physical and mental health. At present, there are about 300 million asthmatics in the world, and about 30 million asthmatics in China. [0005] Drugs used to treat asthma can be divided into two categories: controller drugs and reliever drugs. Controlling drugs refer to drugs that mainly achieve clinical control of asthma through anti-inflammatory effects, including inhaled glucocorticoids, leukotriene modulators, long-a...
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