Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines
A technology of piperidine and naphthylmethyl, applied in the field of preparation of chiral 8-(3-amino-piperidin-1-yl)-xanthine, can solve the problem of 8-(3-aminopiperidine-1- base)-xanthine unfavorable applicability and other issues
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Embodiment 1
[0039] D-tartrate of the R enantiomer of 3-(phthalimido)piperidine
[0040] a. Hydrogenation:
[0041]
[0042] 10.00kg (106.25mol) of 3-aminopyridine, 500g of industrial-grade activated carbon and 65 liters of acetic acid were first charged into the hydrogenation reactor. 50 g of Nishimura catalyst (commercially available rhodium / platinum hybrid catalyst) was slurried in 2.5 liters of acetic acid and flushed in 2.5 liters of acetic acid. Hydrogenation was performed at 50° C. under a hydrogen pressure of 100 bar until hydrogen uptake ceased, followed by post-hydrogenation at 50° C. for 30 minutes. The catalyst and charcoal were filtered off and washed with 10 L of acetic acid. The product solution was subjected to further reactions without purification.
[0043] The reaction can also be performed under less stringent pressures.
[0044] b. Acylation
[0045]
[0046] Firstly, 15.74kg (106.25mol) of phthalic anhydride was charged into the reactor. and mixed with the f...
Embodiment 2
[0054] Synthesis of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiper Pyridin-1-yl)-xanthine
[0055] a.2-Chloromethyl-4-methylquinazoline
[0056]
[0057] First charge 10.00kg (73.98mol) of 2-aminoacetophenone and add 24.5 liters of 1,4-bis alkyl. The solution was cooled to 10°C and mixed with 16.72 kg (458.68 mol) of hydrogen chloride introduced. The reaction mixture was warmed to 22-25°C. Hydrogen chloride was reintroduced at this temperature. At about half of the total charge, the mixture was cooled to -10°C and the charge continued. Subsequently, the resulting suspension was left at -10°C overnight. At -10°C, add 6.70 kg (88.78 mol) of chloroacetonitrile in 2.5 liters of 1,4-bis alkane solution. Fill the feed vessel with 2 liters of 1,4-di alkyl. Afterwards, the contents of the reactor were warmed to 6°C and stirred for an additional approximately 2 hours.
[0058] A mixture of 122 liters of water and 62.04 kg (775.31 mol)...
Embodiment 3
[0076] 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidine -1-yl)-xanthine
[0077] a. 3-cyano-2-(chloromethyl)-pyridine
[0078] 165.5 g (0.98 mol) of 2-hydroxymethyl-3-pyridine carboxamide (pyridinecarboxamide) and 270 ml of phosphorus oxychloride (phosphorus oxychloride) were heated together at 90-100° C. for 1 hour. The reaction mixture was cooled to room temperature and then about 800 ml of water was added dropwise at 50-60°C. After the phosphorus oxychloride is hydrolyzed, it is neutralized with sodium hydroxide solution under cooling, and the product is precipitated during this period. It was filtered, washed with 300 ml of water and then dried at 35-40°C.
[0079] Yield: 122.6 g (82% of theory)
[0080] Alternative to step a: 3-cyano-2-(chloromethyl)pyridine
[0081]20.0 g (131.45 mmol) of 2-hydroxymethyl-3-pyridinecarboxamide were suspended in 110 ml of acetonitrile and heated to 78°C. Within 15 minutes, 60.65 g (395.52 mmol) of ...
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