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Preparation method of formoterol key intermediate

A technology for formoterol and intermediates, which is applied in the preparation of organic compounds, the preparation of carboxylic acid amides, chemical instruments and methods, etc., can solve problems such as not meeting new standards

Active Publication Date: 2019-12-31
上海天慈中商药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, according to literature reports: the chiral alcohol intermediate obtained by reduction by this method has a chiral purity of only about 97%, even after nitro reduction, formylation reaction and refining purification, the chiral purity is only about 99%, compared with the current Commonly required by the pharmaceutical industry, the method does not meet current new standards

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  • Preparation method of formoterol key intermediate
  • Preparation method of formoterol key intermediate
  • Preparation method of formoterol key intermediate

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preparation example Construction

[0054] The present invention provides a formoterol intermediate represented by formula I (namely (R)-N-(2-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)phenyl)methane) The preparation method of amide), comprises the following steps:

[0055] (1) Preparation of (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III)

[0056] The raw material 1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (II) was dissolved in the first organic solvent, (3aS-cis)-(-)-3 was added, 3a,8,8a-Tetrahydro-2H-indeno[1,2-d]oxazole-2-isopropylborane (IV), add borane dimethyl sulfide, complete the addition, at a suitable temperature Carry out the reaction, after the reaction is complete, through appropriate post-treatment, the product (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III) is obtained;

[0057] (2) Preparation of (R)-N-(2-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)phenyl)carboxamide (I)

[0058] (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III) prepared in step (1) was dissolved in the sec...

Embodiment 1

[0081] Preparation of (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III).

[0082] Add 1kg1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (II), 10L toluene, 100g (3aS-cis)-(-)-3,3a to the 20L reactor ,8,8a-tetrahydro-2H-indeno[1,2-d]oxazole-2-isopropylborane (IV), add borane dimethyl sulfide 200ml dropwise, control the temperature at 20-25℃, After dropping, stirring for 0.5h, adding 1L acetone dropwise to quench the reaction, decompressing the solvent, adding 5L toluene, 4L water, stirring and separating, the organic phase was decompressed to obtain a yellow oil (R)-1-(4 -(benzyloxy)-3-nitrophenyl)-2-bromoethanol 955g, yield 95%; chiral purity>99.5%. .

Embodiment 2

[0084] Preparation of (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III).

[0085] Add 1.5kg1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (II), 15L tetrahydrofuran, 200g(3aS-cis)-(-)-3 to the 20L reactor, 3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazole-2-isopropylborane (IV), add borane dimethyl sulfide 330ml dropwise, temperature control 10-15℃ , after dripping, stirring for 0.5h, adding 1.5L acetone dropwise to quench the reaction, spin-drying the solvent under reduced pressure, adding 7.5L ethyl acetate, 6L water, stirring and separating, the organic phase was spin-dried under reduced pressure to obtain a yellow oil (R) -1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol 1402g, yield 93%; chiral purity>99.5%.

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Abstract

The invention provides a preparation method of a formoterol key intermediate (R)-N-(2-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)phenyl)formamide represented by a formula I, wherein asymmetric reduction isperformed by using 1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (II) as a raw material and using (3aS-cis)-(-)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazole-2-isopropylborane (IV) as a catalyst toobtain a chiral alcohol intermediate (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III) with high enantioselectivity, and then nitro reduction and formylation one-pot reaction are performed to obtain a target product represented by the formula I. Compared with the traditional resolution method, the method of the invention has advantages of high chiral purity of the product, short productionperiod, easy operation, mild condition, convenient post-treatment and high yield, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a formoterol key intermediate as shown in formula I. Background technique [0002] (R)-N-(2-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)phenyl)carboxamide has the structure of formula (I): [0003] [0004] Hereinafter all are referred to as compounds of formula (I). The compound of formula (I) is a key intermediate in the synthesis of Formoterolfumarate. [0005] Formoterol fumarate is a β2 sympathomimetic drug, which has the typical basic structure of all sympathomimetic drugs and is a derivative of epinephrine. It binds to the β2 adrenergic receptors in the airway, excites the β2 receptors to relax the tracheal smooth muscle, and achieves the effect of dilating the trachea, thereby relieving symptoms such as wheezing. Formoterol is a drug developed by Japan's Astellas Company for the treatment of asthma and chronic obstructive pulmonary di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/25
CPCC07C231/02C07C201/12C07C233/25C07C205/37Y02P20/55
Inventor 李勇刚李函璞马西来池王胄王卓
Owner 上海天慈中商药业有限公司