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Salmeterol preparation method

A technology for preparation steps and compounds, applied in the preparation of carboxylates, chemical instruments and methods, preparation of hydroxyl compounds, etc., can solve the problems of excessive use of protective groups, large losses, long reaction steps, etc., to avoid high vacuum or Column chromatographic separation, lower raw material cost, and easy availability of raw materials

Active Publication Date: 2015-07-01
ASYMCHEM LAB TIANJIN +4
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In summary, the main problems in the synthetic route of salmeterol are: (1) the price of the key intermediate 4-phenylbutanol (compound 7) is relatively high, and a low-cost synthetic route needs to be developed; (2) The purification of most intermediates is difficult, resulting in a large loss in the purification process of the final product; (3) Excessive use of protective groups leads to longer reaction steps

Method used

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Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1: a kind of method for preparing salmeterol, it is characterized in that concrete preparation steps are as follows:

[0039] (1) Alkylation reaction: Control the temperature at 25±5°C, add 823.5kg (5mL / g) of tetrahydrofuran, 132.1kg (1Kmol, 1.0equiv.) of dimethyl malonate and 60.0kg of sodium hydride into a 2000L reactor (60%, 1.5Kmol, 1.5 equiv.). Stir the system for 1-2 hours, slowly add 185.0kg (1Kmol, 1.0equiv.) 2-bromoethylbenzene dropwise and keep the system temperature at 25±5°C (if necessary, add an external bath to cool down) until the reaction is complete. Press the system into 1520.0 kg of saturated ammonium chloride aqueous solution (8 mL / g) to terminate the reaction. Let stand, separate the liquid, concentrate the organic phase, and directly use it in the next step.

[0040] (2) Decarboxylation reaction: control the temperature at 25±5°C, add DMSO1300kg (10mL / g) and purified water 31.5kg (1.75kmol, 3.5equiv.) 118.1kg of methyl 2-phenylethylmal...

Embodiment 2

[0047] Embodiment 2: a kind of method for preparing salmeterol, it is characterized in that concrete preparation steps are as follows:

[0048] (1) Alkylation reaction: Control the temperature at 25±5°C, add 1.65kg of tetrahydrofuran (10mL / g), 192.2g of diethyl malonate (1.2mol, 1.2equiv.) and tert-butanol into a 10L reactor Sodium 115g (1.2mol, 1.2equiv.). Stir the system for 1-2 hours, slowly add 184.0g (1mol, 1.0equiv.) 2-bromoethylbenzene (compound 2) dropwise and keep the system temperature at 25±5°C (if necessary, add an external bath to cool down) until the reaction is complete. The system was pressed into 1.9 kg of saturated ammonium chloride aqueous solution (10 mL / g) to terminate the reaction. Let stand, separate the liquid, concentrate the organic phase, and directly use it in the next step.

[0049] (2) Decarboxylation reaction: Control the temperature at 25±5°C, add 1.5kg (5mL / g) of DMSO and 54g (3mol, 3.0equiv.) of purified water into the 5L reactor 264g (1mol...

Embodiment 3

[0056] Embodiment 3: a kind of method for preparing salmeterol, it is characterized in that concrete preparation steps are as follows:

[0057] (1) Alkylation reaction: Control the temperature at 25±5°C, add 2.04Kg (15mL / g) of methyl tert-butyl ether and 282g of diisopropyl malonate (1.5mol, 1.5equiv. ) and potassium tert-butoxide 224g (2.0mol, 2.0equiv.). The system was stirred for 1-2 hours, and 184.0 g (1 mol, 1.0 equiv.) of 2-bromoethylbenzene was slowly added dropwise and the temperature of the system was kept at 25±5°C until the reaction was completed. Press the system into 2.9 kg of saturated ammonium chloride aqueous solution (15 mL / g) to terminate the reaction. Let stand, separate the liquid, concentrate the organic phase, and directly use it in the next step.

[0058] (2) Decarboxylation reaction: control the temperature at 25±5°C, add 3.6kg (15mL / g) of n-butanol, 90g (5mol, 5.0equiv.) of purified water, 2-phenylmalonic acid diiso Propyl ester 292g (1mol, 1.0equiv...

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Abstract

The invention discloses a salmeterol preparation method which aims to overcome the defects in the prior art. According to the preparation method, 2-bromine ethylbenzene, which is easier to obtain, is taken as raw material, and the key intermediate 4-phenylbutanol is obtained through condensation, decarboxylation and reduction of 2-bromine ethylbenzene and malonic acid ester; N-benzyl-6-(4-phenyl butyl)-hexylamine is obtained through two-step condensation of 4-phenylbutanol; the key intermediate 5-[2-(benzyl (6-(4-phenyl butyl) hexyl) amino) acetyl] salicylaldehyde is obtained through condensation of N-benzyl-6-(4-phenyl butyl)-hexylamine and 5-chloracetyl-salicylaldehyde; finally, the salmeterol is obtained through simple steps of reduction, deprotection, salifying and the like. According to the preparation method, the technology is stable, the reaction condition is moderate, the selectivity is excellent, the aftertreatment is simple to operate, the intermediates are easily to separate, and the product has high purity and high yield, so that a novel thinking and a novel method for large-scale production of salmeterol are provided.

Description

(1) Technical field: [0001] The present invention relates to the field of organic synthesis pharmacy, in particular to a preparation of salmeterol, whose chemical name is 4-(1-hydroxyl-2-(6-(4-phenylbutoxy)ethylamino)ethyl)-2- (Hydroxymethyl)phenol xinanate method. (2) Background technology: [0002] Salmeterol, chemical name: 4-(1-hydroxy-2-(6-(4-phenylbutoxy)ethylamino)ethyl)-2-(hydroxymethyl)phenol xinanate, is A new selective long-acting β2-receptor agonist whose bronchodilator effect can last for 12 hours in one dose. At the same time, salmeterol has a strong inhibitory effect on the release of allergic reaction mediators from lung mast cells, can inhibit the early and late phase reactions induced by inhaled antigens, and reduce airway hyperresponsiveness. For asthma (including nocturnal asthma and exercise-induced asthma), asthmatic bronchitis and reversible airway obstruction. [0003] Patents US4992474, US20030162840, US20080262267, GB2140800, GB2176476, WO2007045...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/10C07C213/08C07C65/11C07C51/41C07C33/20C07C29/147
Inventor 洪浩马建国李九远黄俊张磊
Owner ASYMCHEM LAB TIANJIN
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