WO1997021711A1 - Procede pour preparer des derives de 4-aminopteridine - Google Patents

Procede pour preparer des derives de 4-aminopteridine Download PDF

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Publication number
WO1997021711A1
WO1997021711A1 PCT/EP1996/005541 EP9605541W WO9721711A1 WO 1997021711 A1 WO1997021711 A1 WO 1997021711A1 EP 9605541 W EP9605541 W EP 9605541W WO 9721711 A1 WO9721711 A1 WO 9721711A1
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WO
WIPO (PCT)
Prior art keywords
general formula
substituted
methanol
meaning given
alkyl group
Prior art date
Application number
PCT/EP1996/005541
Other languages
German (de)
English (en)
Inventor
Martin Eyer
Wolfgang Pfleiderer
Shahriyar Taghavi-Moghadam
Original Assignee
Lonza Ag
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 Lonza Ag filed Critical Lonza Ag
Priority to AU13704/97A priority Critical patent/AU1370497A/en
Publication of WO1997021711A1 publication Critical patent/WO1997021711A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/10—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with an aromatic or hetero-aromatic ring directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4

Definitions

  • the invention relates to a new process for the preparation of 4-amino-dendiates of the general formula
  • Rl is a hydrogen atom, a C j -C4 alkyl group, an aryl group, substituted or unsubstituted, -NH2, -SR 3 , -OR 3 , -NHR 3 or -N (R 3 ) 2, wherein R 3 is a C ⁇ -C4 Is an alkyl group, and R ⁇ is a C 1 -C 4 alkyl group, an aryl group, substituted or unsubstituted. a heteroaryl group, substituted or unsubstituted, or -CH2X.
  • X is a halogen atom, starting from emem 4,5,6-T ⁇ am ⁇ nopy ⁇ m ⁇ d ⁇ n the general formula
  • 4-Aminopte ⁇ d ⁇ ndendvvates are important intermediates for the synthesis of Ptendendvvates such as for the production of folic acid, its antagonist aminoptenen and the cytostatic methotrexate (DE-OS 27 41 383)
  • the CH-PS 630 380 describes a process for the preparation of 2,4-dimin-6-bromomethylpte ⁇ din by direct bromination of 2,4-dimin-6-methylpte ⁇ d ⁇ n.
  • the product is obtained only in moderate yield.
  • the product has Impurities.
  • GB-1 414 752 describes a process for the preparation of 2,4-diamino-6-chloromethylptin in which the educt 2,4-diamino-6-hydroxymethylpteridine is chlorinated using thionyl chloride.
  • a disadvantage of this process is that the preparation of the starting material is complicated or is associated with the formation of troublesome, difficult-to-separate by-products (P.H Boyle, W. Pfleiderer, Chem Ber., 1980, 1 13, pp. 1514 ff.).
  • Yamamoto H et al. (Chem. Ber. 1973, 106, pp. 3175-3193) describe the preparation of 2,4-dimontno-6-phenylpte ⁇ d ⁇ n starting from the educt 2,4,6-t ⁇ acetam ⁇ do-5-nitrosopy ⁇ midin .
  • the starting material is reacted with phenylacetaldehyde.
  • a disadvantage of this process is that the starting material is not accessible in pure form
  • the object of the present invention was both to provide a more economical process for the preparation of 4-aminopte ⁇ d ⁇ ndendvvates and to provide an economical access to the production of peptides such as, for example, folic acid with this process
  • the process for the preparation of 4-aminopeptide dendvates is carried out in such a way that a 4,5,6-thernaturinopylene of the general formula is used
  • Rl has the meaning given or its salt with a compound of the general formula
  • the 4,5,6-triaminopy ⁇ mid ⁇ ne used as starting materials can be prepared in a known manner.
  • 2,4,5,6-tetraaminopy ⁇ m ⁇ din of formula II (R ⁇ NH2) from 2,4,6-T ⁇ am ⁇ no-5-n ⁇ troso-pyrm ⁇ d ⁇ n by hydrogenation with hydrogen / Raney nickel in water and after the catalyst separation z.
  • hydrochloride or hydrobromide salts are expediently used as the salts of the 4,5,6-amino-pyrimide of the general formula II
  • the substituent R ⁇ is a hydrogen atom, a -C4-alkyl group, an aryl group, substituted or unsubstituted, -NH2, -SR 3 , -OR 3 , -NHR 3 or -N (R 3 ) 2- wherein R 3 is a C ] - C4 alkyl group.
  • the substituent R ⁇ represents a Cj-C4-alkyl group, an aryl group, substituted or unsubstituted, a heteroaryl group, substituted or unsubstituted. or - CH2X, where X is a halogen atom
  • a halogen atom can mean fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
  • An unsubstituted aryl group can be phenyl or naphthyl, preferably phenyl.
  • a substituted phenyl group can be tolyl, halophenyl such as fluorine, chlorine, bromine, 3,5-difluorophenyl or C
  • An unsubstituted heteroaryl group can be pyridinyl, py ⁇ dazinyl, a substituted heteroaryl group can be methylpy ⁇ dinyl.
  • a C, -C 4 -alkyl group can be methyl, ethyl, propyl, i-propyl, butyl, i-butyl or t-butyl, preferably Methyl or ethyl, mean
  • the meaning of -SR 3 can be -SCH 3 , -SC 2 H 5 , -SC 3 H 9 , -SC 4 H, 3 , preferably
  • -SCH 3 of -OR 3 , -OCH 3 , -OC 2 H 5 , -OC 3 H 9 , -OC 4 H 13 , preferably -OCH 3 , of -NHR 3 , -NHCH 3 , -NHC 2 H 5 ; of -N (R 3 ) 2 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N (C 3 H 7 ) 2 , -N (C 4 H,) 2 , preferably -N (CH 3 ) 2 .
  • the reaction is expediently carried out in an inert solvent.
  • Polar protic or polar aprotic solvents can be used as inert solvents.
  • Water or C 1 -C 4 alcohols can be used as the polar protic solvent.
  • Methanol, ethanol, propanol or butanol, in particular methanol, is expediently used as the C 4 -C 4 alcohol.
  • Dimethylformamide or dimethylacetamide can be used as the polar aprotic solvent
  • the suitable solvents can be used individually or as a mixture
  • the reaction is expediently carried out at a temperature from 0 ° C. to the reflux temperature of the corresponding solvent, preferably at 20 to 70 ° C.
  • the 4-aminopte ⁇ d ⁇ nde ⁇ vate can be isolated by workup methods customary in the art and then either in a manner known per se
  • R has the meaning given and R 2 denotes -CH 2 X, where X is a halogen atom, hydrolyzed (for example according to J. Heterocyclic Chem., 1987, pp. 279ff) and / or by reaction with a compound of the general formula
  • R 4 is a glutamic acid residue and R 5 is C, -C 4 alkyl or em hydrogen atom m is a pentene dvate of the general formula
  • Example 3a 1.09 g (5.00 mmol) of 2,4,5,6-tetraaminopy ⁇ m ⁇ d ⁇ nd ⁇ hydrochIo ⁇ d in a mixture of 47.5 ml of methanol and 2.5 ml of dimethylacetamide at 63 ° C. for 3 minutes with 0, 91 g of chlororuvaldoxime (7.49 mmol) were added to 10 ml of methanol. The mixture was then heated at the reflux temperature until a clear solution had formed after 2.5 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un nouveau procédé pour préparer des dérivés de 4-aminoptéridine de formule générale (I) dans laquelle R1 représente un atome d'hydrogène, un groupe alkyle C¿1?-C4, un groupe aryle substitué ou non substitué, -NH2, -SR?3, -OR3, -NHR3¿ ou bien -N(R3)2, où R3 désigne un groupe alkyle C¿1? -C4, et R?2¿ désigne un groupe alkyle C¿1?-C4, un groupe aryle substitué ou non substitué, un groupe hétéroaryle substitué ou non substitué, ou bien -CH2X où X est un atome d'halogène. Ce procédé s'effectue par la réaction d'un 4,5,6-triaminopyrimidine de formule générale (II), dans laquelle R?1¿ a la notation précitée, ou bien de son sel, avec un composé de formule générale (III), dans laquelle R2 a la notation précitée, jusqu'à obtention du produit final de formule (I).
PCT/EP1996/005541 1995-12-12 1996-12-11 Procede pour preparer des derives de 4-aminopteridine WO1997021711A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13704/97A AU1370497A (en) 1995-12-12 1996-12-11 Process for preparing 4-aminopteridine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH350395 1995-12-12
CH3503/95 1995-12-12
CH2059/96 1996-08-22
CH205996 1996-08-22

Publications (1)

Publication Number Publication Date
WO1997021711A1 true WO1997021711A1 (fr) 1997-06-19

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/005541 WO1997021711A1 (fr) 1995-12-12 1996-12-11 Procede pour preparer des derives de 4-aminopteridine

Country Status (2)

Country Link
AU (1) AU1370497A (fr)
WO (1) WO1997021711A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19944767A1 (de) * 1999-09-17 2001-03-29 Vasopharm Biotech Gmbh & Co Kg N-substituierte 4-Aminopteridine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7691858B2 (en) 2006-04-25 2010-04-06 Targegen, Inc. Kinase inhibitors and methods of use thereof
US8222238B2 (en) 2003-03-25 2012-07-17 Vasopharm Biotech Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
WO2014187274A1 (fr) * 2013-05-24 2014-11-27 苏州明锐医药科技有限公司 Pralatrexate et procédé de préparation d'un intermédiaire de celui-ci

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115583634B (zh) * 2022-09-21 2023-06-06 广东工业大学 一种碳氮聚合物材料的制备方法及应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1414752A (en) * 1974-03-20 1975-11-19 Inst Oncologic Process for the preparation of diamino-pteridyl-methyl- methylamino-benzoyl-glutamic acid derivative
CH630380A5 (de) * 1977-08-12 1982-06-15 Lonza Ag Verfahren zur herstellung von l-methotrexat.
EP0608693A2 (fr) * 1993-01-26 1994-08-03 F. Hoffmann-La Roche Ag Procédé pour la préparation de l'acide folique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1414752A (en) * 1974-03-20 1975-11-19 Inst Oncologic Process for the preparation of diamino-pteridyl-methyl- methylamino-benzoyl-glutamic acid derivative
CH630380A5 (de) * 1977-08-12 1982-06-15 Lonza Ag Verfahren zur herstellung von l-methotrexat.
EP0608693A2 (fr) * 1993-01-26 1994-08-03 F. Hoffmann-La Roche Ag Procédé pour la préparation de l'acide folique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. R. KATRITZKY: "Part 2B; Pteridines", COMPREHENSIVE HETEROCYCLIC CHEMISTRY, vol. 3, XP002028908 *
CHEMICAL ABSTRACTS, vol. 101, no. 25, 17 December 1984, Columbus, Ohio, US; abstract no. 230476t, page 767; XP002028909 *
SHEY, CHUNG FENG ET AL.: "Synthesis of 3,4-diamino-6-substituted pteridine", SHI TA HSUEH PAO, vol. 29, 1984, pages 631 - 43 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19944767A1 (de) * 1999-09-17 2001-03-29 Vasopharm Biotech Gmbh & Co Kg N-substituierte 4-Aminopteridine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US8222238B2 (en) 2003-03-25 2012-07-17 Vasopharm Biotech Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
US9382252B2 (en) 2003-03-25 2016-07-05 Vasopharm Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
US9422289B2 (en) 2003-03-25 2016-08-23 Vasopharm Gmbh Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species
US7691858B2 (en) 2006-04-25 2010-04-06 Targegen, Inc. Kinase inhibitors and methods of use thereof
WO2014187274A1 (fr) * 2013-05-24 2014-11-27 苏州明锐医药科技有限公司 Pralatrexate et procédé de préparation d'un intermédiaire de celui-ci

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Publication number Publication date
AU1370497A (en) 1997-07-03

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