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.
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[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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