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Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines

A technology of piperidine and naphthylmethyl, applied in the field of preparing chiral 8--xanthine, can solve problems such as unfavorable applicability of 8-(3-aminopiperidin-1-yl)-xanthine

Active Publication Date: 2007-10-03
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These circumstances are unfavorable for the suitability of the known industrial preparation of enantiomerically pure 8-(3-aminopiperidin-1-yl)-xanthine

Method used

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  • Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines
  • Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines
  • Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines

Examples

Experimental program
Comparison scheme
Effect test

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 10.00 kg (73.98 mol) of 2-aminoacetophenone and add 24.5 liters of 1,4-dioxane. 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. A solution of 6.70 kg (88.78 mol) of chloroacetonitrile in 2.5 liters of 1,4-dioxane was added within one hour at -10°C. The feed vessel was flushed with 2 liters of 1,4-dioxane. 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 an...

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-pyridinecarboxamide (pyridinecarboxamide) and 270 ml of phosphorus oxychloride (phosphorus oxychloride) were heated 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 phosphoru...

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Abstract

Method for preparing 8-(3-aminopiperidin-1-yl)-xanthine derivatives (I) and their enantiomers and salts. Method for preparing 8-(3-aminopiperidin-1-yl)-xanthine derivatives of formula (I) and their enantiomers and salts by: (a) reacting an 8-X-xanthine (III) with 3-phthalimidopiperidine (A), or its enantiomer; (b) deprotecting the product (II); and (c) optionally conversion to salt. X : halo or sulfonate ester, especially bromo; R 1>phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, (iso)quinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or phenanthridinylmethyl, all optionally substituted by one or two, same or different, Ra; R 2>1-3C alkyl, cyclopropyl or phenyl; R 3>2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, or 2-(fluoro, chloro, bromo, iodo, methyl, trifluoromethyl or cyano)-benzyl; Ra : hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, di- or tri-fluoromethoxy, or two Ra on adjacent C atoms complete OCH 2O or OCH 2CH 2O Independent claims are also included for the following: (1) (R) and (S)-3-phthalimidopiperidine as new compounds; and (2) methods for preparing the compounds of (1). [Image] [Image] - ACTIVITY : Antidiabetic; Antiarthritic; Anorectic; Osteopathic. No details of tests for these activities are given. - MECHANISM OF ACTION : Inhibition of dipeptidylpeptidase IV.

Description

technical field [0001] The present invention relates to an improved process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines, their enantiomers and their physiologically tolerable salts. Background technique [0002] 8-(3-aminopiperidin-1-yl)-xanthine of the following general structure [0003] [0004] where R 1 is, for example optionally substituted arylmethyl or optionally substituted heteroarylmethyl, R 2 is, for example, alkyl, and R 3 is, for example, optionally substituted benzyl or straight-chain or branched alkenyl or alkynyl, as already known from international patent applications WO 02 / 068420, WO 04 / 018468, WO 04 / 018467, WO 2004 / 041820 and WO 2004 / 046148, which describes compounds having valuable pharmacological properties including, inter alia, the inhibition of the activity of the enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, such compounds are suitable for preventing or treating diseases or symptoms associated with increased DPP-I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04A61K31/522
CPCC07D473/04C07D473/06C07D401/04C07B2200/07A61P19/00A61P19/02A61P19/10A61P29/00A61P3/00A61P3/10A61P3/04A61P3/08A61P37/06A61P43/00A61K31/522
Inventor 沃尔德马·弗兰格尔索尔斯藤·帕彻托马斯·尼古拉阿迪尔·杜兰
Owner BOEHRINGER INGELHEIM INT GMBH
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