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Process for the preparation of tryptase inhibitors

A technology of solvents and compounds, applied in the field of application in the preparation of such compounds, capable of solving defects, dangers, etc.

Inactive Publication Date: 2007-04-18
AVENTIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Certain processes for the preparation of compounds of formula I are also disclosed in these patent applications, however, these processes have serious drawbacks and dangers, especially when large-scale preparation of compounds of formula I is required

Method used

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  • Process for the preparation of tryptase inhibitors
  • Process for the preparation of tryptase inhibitors
  • Process for the preparation of tryptase inhibitors

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preparation example Construction

[0215] In a specific embodiment, the present invention also provides 4-[3-(aminomethyl)phenyl]-1-[5-(2-fluorophenylethynyl)-2-furoyl, which can be used in the present invention ] The new intermediate of the preparation method of piperidine or its salt, which comprises:

[0216] 1-(3-Bromobenzyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane;

[0217] 1-[3-(1-Benzyl-4-hydroxypiperidin-4-yl)benzyl]-2,2,5,5-tetramethyl-1-aza-2,5-disilacycle Pentane;

[0218] 3-(1-benzyl-4-hydroxypiperidin-4-yl)benzylamine or its salt;

[0219] 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzylamine or its salt;

[0220] tert-butyl 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzylcarbamate or its salts;

[0221] 3-(4-pyridyl)benzaldehyde oxime or its salt;

[0222] 3-(4-pyridyl)benzylamine or its salt;

[0223] tert-butyl 3-(4-pyridyl)benzylcarbamate or a salt thereof; and

[0224] 4-[3-(tert-butoxycarbonylaminomethyl)phenyl]-1-[5-bromo-2-furoyl]piperidine;

[0225] And in another specif...

Embodiment 1

[0287] 4-[3-(tert-Butoxycarbonylaminomethyl)phenyl]piperidine

[0288] a) 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane

[0289] To a stirred suspension of 3-bromobenzylamine hydrochloride (310 g, 1.39 mol) in dichloromethane (2 L) was added triethylamine (437 g, 4.32 mol) followed by 1,2-bis( Chlorodimethylsilyl)ethane (300 g, 1.39 mol) in dichloromethane (700 mL). The resulting suspension was stirred for 30 minutes, then filtered. The filtrate was concentrated in vacuo and pentane was added. After filtration, the solvent was removed in vacuo to give the title compound (435 g, 95%) as a colorless oil. 1 H NMR (CDCl 3 ) δ = 7.4-7.1 (m, 4H), 4.0 (s, 2H), 0.8 (t, 4H), 0.2 (s, 12H).

[0290] b) tert-butyl 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzylcarbamate

[0291] To 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (435g, 1.33mol) in tetrahydrofuran at -60°C To the solution (4 L) was added a 2.5M n-butyllithium (n-BuLi) soluti...

Embodiment 2

[0300] 4-[3-(tert-Butoxycarbonylaminomethyl)phenyl]piperidine p-toluenesulfonate

[0301] a) 3-(4-pyridyl)benzaldehyde oxime hydrochloride

[0302] 3-(4-Pyridyl)benzaldehyde (100 g, 546 mmol) was dissolved in methanol (500 mL), and then a methanolic solution (260 mL) of hydroxylamine hydrochloride (40.2 g, 573 mmol) was added. After complete conversion, a small sample of the reaction mixture was concentrated in vacuo. MS (DCI) m / z 181.1, 199.1, 200.2. 1 H-NMR (400MHz, DMSO-d 6 )δ=7.56(t, J=7.7Hz, 1H), 7.70-7.75(m, 3H), 7.79-7.83(m, 1H), 7.97-7.99(m, 1H), 8.25(s, 1H), 8.65 -8.67 (m, 2H), 11.4 (s, 1H).

[0303] b) 3-(4-pyridyl)benzylamine hydrochloride

[0304] The methanol solution of 3-(4-pyridyl)benzaldehyde oxime hydrochloride obtained above was added to palladium on carbon (13.1 g, 5% Pd / C). The mixture was stirred at 35°C under a hydrogen pressure of 500 kPa until no more hydrogen was consumed. The catalyst was filtered off. HPLC showed complete conversion. A smal...

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Abstract

This invention is directed to processes for the preparation of compounds of the formula I and their salts, <CHEM> which are useful as tryptase inhibitors, to intermediates useful in the preparation of such compounds, to processes for the preparation of such intermediates, and to the use of such intermediates for the preparation of such compounds.

Description

[0001] The present invention relates to a preparation method of a compound that can be used as a tryptase inhibitor, to an intermediate that can be used to prepare this type of compound, to a preparation method of this type of intermediate, and to the use of this type of intermediate in the preparation of this type of compound application. Background of the invention [0002] Mast cell-mediated inflammatory disorders, especially asthma, are a growing public health concern. Asthma is often characterized by progressive hyperresponsiveness of the trachea and bronchi to immunospecific allergens and general chemical or physical stimuli, leading to chronic inflammation. Leukocytes containing IgE receptors, especially mast cells and basophils, are present in the epithelium and underlying smooth muscle tissue of the bronchi. These leukocytes are initially activated by specific inhaled antigens binding to IgE receptors, and then release a number of chemical mediators. For example, de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/10C07D211/02C07D211/26C07F7/10C07D213/38C07D213/53
CPCC07F7/10C07D213/38C07D211/70C07D211/52C07D405/08C07D213/53C07D405/06C07C303/32C07D211/26C07D213/40
Inventor C-D·格拉夫C·塔佩尔佐芬A·W·斯莱德斯基
Owner AVENTIS PHARMA INC
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