EP0652880A1 - Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine - Google Patents

Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine

Info

Publication number
EP0652880A1
EP0652880A1 EP94916973A EP94916973A EP0652880A1 EP 0652880 A1 EP0652880 A1 EP 0652880A1 EP 94916973 A EP94916973 A EP 94916973A EP 94916973 A EP94916973 A EP 94916973A EP 0652880 A1 EP0652880 A1 EP 0652880A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
substituted
phenyl
cooh
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94916973A
Other languages
German (de)
English (en)
Inventor
Ulrike Küfner-Mühl
Sven Lüttke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP0652880A1 publication Critical patent/EP0652880A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to an improved process for the preparation of xanthine derivatives substituted in the 8-position.
  • Xanthine derivatives have valuable phamacological properties as adenosine antagonists. Of particular interest are synthetic processes that make it possible to produce xanthine derivatives in chemically and optically high yields. Xanthine derivatives are usually synthesized by a ring-closing reaction of the correspondingly substituted aminouracils under alkaline conditions - such as, for example, aqueous sodium hydroxide solution - at elevated temperatures. In many cases, at least partial racemization takes place under these reaction conditions.
  • R1 hydrogen, Ci-Cß-alkyl, preferably Cß-alkyl, especially n-propyl, C3-C6-alkenyl, preferably allyl or Cs-Cß-alkynyl;
  • R2 is hydrogen, a C-
  • R 2 is phenyl-C-
  • R is a radical of the formula
  • AC 2 -C6-alkynylene where A is a C- or N-linked 5- or 6-membered heterocyclic ring which contains nitrogen, oxygen or sulfur as heteroatoms, which may be one or more C 1 -C 4 -alkyl groups, Halogen, -ORs, -NO 2 , -
  • R3 is an optionally substituted C-linked saturated or unsaturated five-, six- or seven-membered heterocyclic ring which contains one or more heteroatoms selected from the group consisting of oxygen and sulfur,
  • R3 is a C4 to Cs cycloalkene which can be substituted by C 2 to C4 alkenyl
  • R3 is a C4 to C ⁇ - preferably C5 and C6-cycloalkanone or a C4 to C ⁇ - preferably C5 and Cß-cycloalkanol, which is in the ⁇ -position by C 2 to CQ - preferably C to C4-alkenyl, C 2 to CQ - preferably C 2 to C4-alkynyl, optionally substituted benzyl, CH 2 OR4, CH 2 COOH, can be substituted,
  • R3 is preferably a C3 to CQ - C5 or Cß-cycloalkane, which may be replaced by C-
  • to CQ - preferably C ⁇ to C4-alkyl, CH 2 ,
  • to CQ preferably C-j to C4 alkyl, vinyl, allyl, optionally substituted phenyl, optionally substituted C-
  • R3 is a ketal of the general formula
  • Rb mean C1-C4 alkyl
  • Ra and Rb together form a C 2 or C3 alkylene bridge, which can optionally be substituted once or twice by Ci-Cs-alkyl:
  • R3 is an optionally substituted radical of the formula
  • R3 is a radical of the formula
  • R3 is phenyl which is optionally substituted by -OH, halogen, -ORß, C ⁇
  • R3 is a norbornane, norbornene, a C3-C6 dicycloalkylmethyl, adamantane or noradamantane radical;
  • R3 -CH CH-phenyl, where the phenyl ring is substituted one or more times by methoxy, hydroxy or halogen;
  • R3 is a [3,3,0] bicyclooctane; a [3,3,0] bicyclooctan-2-yl,
  • R3 is a C-linked piperidine or furan;
  • R4 is hydrogen, methyl or benzyl, where the benzyl group can be substituted by 1 to 3 methoxy groups; CH 3 -0-CH 2 - CH 3 -S-CH 2 -,
  • - C4-alkyl which is optionally substituted by OH, NH 2 or NRßR7, preferably -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -OH;
  • RQ is hydrogen, an optionally substituted cycloalkyl group with 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group with up to 10 carbon atoms, which are optionally substituted by hydroxyl, phenyl, substituted phenyl, amino, substituted amino, C-
  • R7 is hydrogen, an optionally substituted cycloalkyl group with 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group with up to 10 carbon atoms, which are optionally substituted by hydroxyl, phenyl, substituted phenyl, amino, substituted amino, C-
  • Rg C-
  • amides A or B wherein R-
  • Suitable solvents are, for example, water-miscible solvents such as methanol, ethanol, isopropanol, propanol or tetrahydrofuran. In individual cases, it may be necessary to protect hydrolysis-sensitive functional residues with a removable protective group.
  • an aqueous solution of lithium hydroxide hydrate is added, the concentration of LiOH being approximately 0.5 to 2 mol / ltr, preferably 1 to 1.5 mol / ltr.
  • a 4 to 10-fold, preferably 5-8-fold excess of lithium hydroxide is used.
  • the cyclization to xanthine is preferably carried out at room temperature, but elevated temperatures, for example under reflux conditions, can also be carried out to shorten the reaction time.
  • elevated temperatures for example under reflux conditions
  • the completeness of the cyclization can be checked, for example, by means of thin layer chromatography. Further work-up is carried out by adjusting the reaction solution to pH 6.5-7, and the crystals which precipitate out are isolated by customary methods. Alternatively, the reaction solution can be adjusted to pH 4, for example with hydrochloric acid. The organic solvent is then distilled off and the remaining aqueous residue is extracted with an organic solvent and worked up in a conventional manner.
  • R-] hydrogen, methyl, ethyl, propyl or allyl, preferably n propyl
  • R 2 is hydrogen, methyl, ethyl, propyl or allyl, preferably n propyl;
  • R3 is a cyclopentane, cyclopentanol or cyclopentanone is an optionally substituted phenyl
  • R3 is an optionally substituted adamantane, norbonane or norbornene
  • R3 is a camphanic acid residue or a derivative thereof
  • R4 is hydrogen or benzyl.
  • Type A uracil derivatives in which the acid amide group is arranged in the 5-position of the uracil are preferred.
  • 1,3-Dipropyl-8- (3-oxocyclopentyl) xanthine and its two optically active isomers have valuable pharmacological properties as adenosine antagonists and are medicinal products for the symptomatic therapy of degenerative diseases of the elderly, e.g. Dementia senilis and Alzheimer's disease of great interest.
  • the synthesis of the racemate and the optically active isomers is described for the first time in European patent application 374 808.
  • ketal is the preferred protecting group, other 5- and 6-ring ketals can also be used as protecting groups according to the invention.
  • the hydrolysis of the ester function while maintaining the optical activity is of crucial importance for the process according to the invention.
  • the solvents used are hydrophilic solvents - water-miscible solvents, such as, for example, tetrahydrofuran, methanol, ethanol, propanol and isopropanol in a mixture with Suitable for water. Tetrahydrofuran / H 2 O and ethanol / H2 ⁇ are preferred.
  • the ketal VII is prepared starting from the carboxylic acid IV by reaction with 5,6-diamino-1,3-dipropyluracil via the amide VI, which is then cyclized to the xanthine using lithium hydroxide hydrate.
  • the protective group is then split off using concentrated mineral acid.
  • the protective group is split off under the usual conditions known from the literature, the preferred solvent is ethanol / water, the preferred mineral acid is concentrated sulfuric acid.
  • 1.0 mol of starting material is optionally dissolved in 2250 ml of ethanol or tetrahydrofuran / water mixture (1000 ml / 3330 ml) and a solution of 6.1 mol - 7.5 mol of lithium hydroxide hydrate in 5000 ml - 6150 ml of water is added at room temperature.
  • the reaction mixture is optionally stirred for 16 h at room temperature or 2 h at room temperature and then for 2.5 h while refluxing. The completeness of the implementation is checked by means of DC control.
  • both the racemic 1,3-dipropyl-8- (3-oxocyclopentyl) xanthine I, the R (+) - 1,3-dipropyl-8- (3-oxocyclopentyl) xanthine la and the S ( -) - 1, 3-Dipropyl-8- (3-oxocyclopentyl) - xanthine Ib are prepared, according to the optical activity of the 3-oxocyclopentane carboxylic acid Ila (OCC) used.
  • OCC 3-oxocyclopentane carboxylic acid Ila
  • the OCC used should have an optical purity of> 99%, since partial racemization of 1-3% can occur in the course of the synthesis (the formation of the amide VI and the subsequent ring closure).
  • phase is separated, the water phase is extracted 3 times with 50 ml of toluene, the combined org. Phases washed 1x with 90 ml 2.5% LiOH solution and 2x with 50 ml H2O. The org. Phase is dried with magnesium sulfate and i.V. constricted. The oily residue is fractionally distilled in a water jet vacuum.
  • a solution of 51.0 g (0.23 mol) of 2-carbomethoxy-8,8-dimethyl-6,10- is added to a suspension of 11.7 g (0.28 mol) of lithium hydroxide hydrate in 1450 ml of H2O. dioxaspiro [4,5] decane in 225 ml tetrahydrofuran (THF) and the mixture is stirred for 1.5 hours at room temperature.
  • the mixture is adjusted to pH 7 with about 150 ml of 4N HCl, then the THF is distilled at a bath temperature of 40 ° C. from.
  • the pH of the water phase is adjusted to pH 4.5, saturated with NaCl and extracted a total of four times with 400 ml of ether. In between, pH 4.5 must be set again.
  • the combined organic phases are dried over Na2S ⁇ 4 and i.V. constricted. The residue is dried for one hour at 100 ° C. in a vacuum drying cabinet. (The substance melts and solidifies again when it cools down.)
  • the amide is very decomposable; it should be handled in a protective gas atmosphere and best implemented immediately. Determining the rotational value or the optical purity at this level is not useful.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé amélioré de préparation de xanthine substituée en 8ème position par réaction alcaline de cyclisation des uraciles correspondants en présence d'hydroxyde de lithium.
EP94916973A 1993-05-18 1994-05-18 Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine Withdrawn EP0652880A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4316576 1993-05-18
DE4316576A DE4316576A1 (de) 1993-05-18 1993-05-18 Verbessertes Verfahren zur Herstellung von 1,3-Dipropyl-8-(3-Oxocyclopentyl)-xanthin
PCT/EP1994/001611 WO1994026743A1 (fr) 1993-05-18 1994-05-18 Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine

Publications (1)

Publication Number Publication Date
EP0652880A1 true EP0652880A1 (fr) 1995-05-17

Family

ID=6488359

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94916973A Withdrawn EP0652880A1 (fr) 1993-05-18 1994-05-18 Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine

Country Status (6)

Country Link
US (1) US5675005A (fr)
EP (1) EP0652880A1 (fr)
JP (1) JPH07509492A (fr)
CA (1) CA2140434A1 (fr)
DE (1) DE4316576A1 (fr)
WO (1) WO1994026743A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4316576A1 (de) * 1993-05-18 1994-11-24 Boehringer Ingelheim Kg Verbessertes Verfahren zur Herstellung von 1,3-Dipropyl-8-(3-Oxocyclopentyl)-xanthin
CN1950324B (zh) 2004-05-11 2010-06-09 株式会社可乐丽 环戊酮-2,3,5-三羧酸三酯的制备方法
US7598379B2 (en) * 2005-02-25 2009-10-06 Pgx Health, Llc Methods for the synthesis of unsymmetrical cycloalkyl substituted xanthines
WO2006120755A1 (fr) * 2005-05-10 2006-11-16 Kuraray Co., Ltd. Procede de production d'une forme acetal cyclique de l'acide 3-oxocyclopentane-1-carboxylique
CA2625668A1 (fr) * 2005-10-24 2007-05-03 Peter John Harrington Preparation de cetones cetalisees, cycliques, par rearrangement de favorskii et leur utilisation pour la preparation d'un activateur de la glucokinase 70
WO2007077111A1 (fr) * 2005-12-30 2007-07-12 F. Hoffmann-La Roche Ag Composés et méthodes pour la synthèse de carbazole
ES2595240T3 (es) 2012-07-09 2016-12-28 Lupin Limited Derivados de tetrahidroquinazolinona como inhibidores de PARP

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2091249A (en) * 1980-12-23 1982-07-28 Fordonal Sa Xanthine derivatives
US4755517A (en) * 1986-07-31 1988-07-05 Warner-Lambert Company Derivatives of xanthine, pharmaceutical compositions and methods of use therefor
CH670090A5 (fr) * 1986-10-27 1989-05-12 Nestle Sa
DE8817122U1 (de) * 1988-12-22 1993-02-04 Boehringer Ingelheim Kg, 55218 Ingelheim Neue Xanthinderivate mit Adenosinantogenistischer Wirkung
JP2843634B2 (ja) * 1989-03-06 1999-01-06 協和醗酵工業株式会社 キサンチン誘導体
DE4019892A1 (de) * 1990-06-22 1992-01-02 Boehringer Ingelheim Kg Neue xanthinderivate
EP0541120B1 (fr) * 1991-11-08 1999-05-26 Kyowa Hakko Kogyo Co., Ltd. Dérivés de Xanthine pour le traitement de la démence
IT1260444B (it) * 1992-01-24 1996-04-09 Mario Brufani Derivati della 8-(1-amminocicloalchil)1,3-dialchilxantina, procedimenbto di preparazione e loro composizioni farmaceutiche antidepressive, nootropiche e psicostimolanti
US5342841A (en) * 1992-03-12 1994-08-30 Kyowa Hakko Kogyo Co., Ltd. Xanthine derivatives
TW252044B (fr) * 1992-08-10 1995-07-21 Boehringer Ingelheim Kg
DE4316576A1 (de) * 1993-05-18 1994-11-24 Boehringer Ingelheim Kg Verbessertes Verfahren zur Herstellung von 1,3-Dipropyl-8-(3-Oxocyclopentyl)-xanthin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9426743A1 *

Also Published As

Publication number Publication date
DE4316576A1 (de) 1994-11-24
WO1994026743A1 (fr) 1994-11-24
JPH07509492A (ja) 1995-10-19
US5675005A (en) 1997-10-07
CA2140434A1 (fr) 1994-11-24

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