EP2922824A1 - Neues verfahren zur synthese von trichlorpyrimidinaminderivaten - Google Patents

Neues verfahren zur synthese von trichlorpyrimidinaminderivaten

Info

Publication number
EP2922824A1
EP2922824A1 EP13805592.6A EP13805592A EP2922824A1 EP 2922824 A1 EP2922824 A1 EP 2922824A1 EP 13805592 A EP13805592 A EP 13805592A EP 2922824 A1 EP2922824 A1 EP 2922824A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
synthesis
amino
trichloro
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Withdrawn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
EP13805592.6A
Other languages
English (en)
French (fr)
Inventor
László Czibula
László Dobay
Krisztina SZAVICSKÓ
Dorottya Kiss-Bartos
Judit NAGYNÉ BAGDY
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.)
Richter Gedeon Nyrt
Original Assignee
Richter Gedeon Nyrt
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 Richter Gedeon Nyrt filed Critical Richter Gedeon Nyrt
Publication of EP2922824A1 publication Critical patent/EP2922824A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the invention relates to a new process for the synthesis of 2-(N-methyl)-amino-4,5,6- trichloro-l,3-pyrimidine of formula (I), as well as the new compounds of formula (II) and (III) synthesized as intermediates in the process.
  • 2-(N-methyl)-amino-4,5,6-trichloro-l,3-pyrimidine of formula (I) can preferably be used in the synthesis of drug substances, for example in the synthesis of compounds described in the Hungarian patent application HU20070000269 of Richter.
  • the compound of formula (I) can be obtained the following way: methyl guanidine hydrochloride and diethylmalonate are condensed in the presence of sodium ethoxide in ethanol, then the obtained product is transformed into the desired compound with phosphorous(V) oxychloride.
  • the invention relates to the process for the synthesis of compound of formula (I) which consist of the following steps:
  • the chlorination reaction is preferably carried out between 25 and 105°C, more preferably between 75 and 80°C.
  • apolar solvents can preferably be used.
  • solvents are for example: toluene, xylene or chlorobenzene.
  • the chlorination reaction is preferably carried out in the presence of equimolar (1-1.2 mol/mol) dimethyl formamide.
  • the invention relates to the compound of formula (II), obtained in the chlorination reaction carried out in the presence of dimethyl formamide, the chemical name of which is 2-(N N'-dimethylamino-methylene)-amino-4,5,6-trichloro-l,3-pyrirnidine.
  • the invention relates to the observation that depending on the quality of the acidic hydrolysis compound of formula (III) or compound of formula (IV) is formed from compound of formula (II):
  • the acidic hydrolysis can be carried out with an acid, preferably with a strong mineral acid or an organic sulfonic acid, such as for example hydrochloric acid, sulfuric acid, phosphoric acid, p-toluene sulfonic acid.
  • a strong mineral acid or an organic sulfonic acid such as for example hydrochloric acid, sulfuric acid, phosphoric acid, p-toluene sulfonic acid.
  • the mild acidic hydrolysis is typically carried out with a small excess of acid, preferably 2.5- 3.5 equivalent of hydrochloric acid calculated on the amount of compound of formula (II).
  • the strong acidic hydrolysis is typically carried out with a large excess of acid, preferably 9- 10 equivalent of hydrochloric acid.
  • the invention relates to the new compound of formula (III) obtained from the compound of formula (II) under mild acidic conditions.
  • This reaction is preferably carried out in a C C 4 alcohol type solvent.
  • the reaction is most preferably carried out in isopropanol, because in this case the compound of formula (III) precipitates in good yield.
  • the invention relates to the surprising observation that during the alkylation reaction of the compound of formula (IV) the monoalkylated product can only be synthesized under phase transfer conditions.
  • the compound of formula (IV) can be transformed into the desired compound of formula (I) in good yield by using generally applied methylating agents, for example: methyl halogenides, dimethyl sulfate, under phase transfer conditions.
  • methylating agents for example: methyl halogenides, dimethyl sulfate
  • organic ammonium salts as phase transfer catalysts, such as for example benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate.
  • the alkylation is preferably carried out between 0 and 20°C, more preferably between 0 and 5°C.
  • the alkylation can be carried out in the presence of methyl iodide, but for industrial scale the most applicable solution is the use of dimethyl sulfate. Structure elucidation of the compounds was carried out by NM R spectroscopy.
  • Example 1 The invention is illustrated by the following not limiting examples.
  • Example 1 The invention is illustrated by the following not limiting examples.
  • the reaction mixture was stirred at 40-42 °C for 30 min, then at 20-22 °C for 1 h.
  • the precipitated almost white product was filtered and washed with 150 ml of ion exchanged water in three portions.
  • the product was dried at maximum 60 °C in a vacuum oven for 3 h, then at 100-102 °C for further 5 h till constant weight.
  • the mixture was warmed to 75-78 °C and stirred at this temperature for 7 h.
  • the reaction was monitored by thin layer chromatography.
  • the mixture was cooled to 20-22 °C, stirring was stopped, the lower phase containing the product was separated and added to a mixture of 300 ml of concentrated NH 3 and 300 g of ice.
  • the obtained two- phase mixture was separated: the aqueous phase was extracted with 50 ml of toluene, the combined organic phases were washed with a solution of 25 g of sodium chloride and 130 ml of water.
  • the reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20- 22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
  • the reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20- 22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
  • the mixture was stirred at this temperature for 30 min, then cooled to 10- 15°C and stirred at this temperature for 1 h.
  • the precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
  • the reaction was monitored by thin layer chromatography. After completion of the reaction 120 ml of water and 40 ml of dichloromethane were added keeping the temperature below 20 °C. The phases were separated, the organic phase was extracted with 120 ml of water in two portions, then a solution of 6 g of sodium chloride and 34 ml of water. The organic phase was concentrated in vacuum, the residue was refluxed in 80 ml of isopropanol for 2 h, then cooled to 20-25 °C and stirred at this temperature for 2 h. The crystals were filtered and washed with 40 ml of isopropanol (20-25 °C) in two portions.
  • the precipitated crystals were filtered, washed with 3x50 I of water and dried at maximum 30 °C till constant weight.
  • the reaction was monitored by thin layer chromatography (samples were taken in every hour). After completion of the reaction 100 I of water and 33.3 I of dichloromethane were added keeping the temperature below 20 °C. The phases were separated, the organic phase was extracted with 100 I of water in two portions, then a solution of 5 kg of sodium chloride and 28 I of water. The organic phase was concentrated in vacuum, the residue was dissolved in 66.7 I of isopropanol in a 250 I autoclave and it was refluxed for 2 h, then cooled to 20-25 °C and stirred at this temperature for 2 h. The crystals were filtered and washed with 33 I of isopropanol (20-25 °C) in two portions.
  • the wet (with isopropanol) 2-(N-methyl)-amino-4,5,6-trichloro-l,3-pyrimidine was refluxed in 17 I of methanol for 1 h, then cooled to 20-25 "and stirred at this temperature for further 1 h. The crystals were filtered, washed with 17 I of methanol in two portions and dried at maximum 50 °C till constant weight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP13805592.6A 2012-11-21 2013-11-20 Neues verfahren zur synthese von trichlorpyrimidinaminderivaten Withdrawn EP2922824A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1200674A HU230149B1 (hu) 2012-11-21 2012-11-21 Új eljárás triklór-pirimidin-amin származékok előállítására
PCT/IB2013/060264 WO2014080341A1 (en) 2012-11-21 2013-11-20 New process for the synthesis of trichloropyrimidine-amine derivatives

Publications (1)

Publication Number Publication Date
EP2922824A1 true EP2922824A1 (de) 2015-09-30

Family

ID=89990948

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13805592.6A Withdrawn EP2922824A1 (de) 2012-11-21 2013-11-20 Neues verfahren zur synthese von trichlorpyrimidinaminderivaten

Country Status (3)

Country Link
EP (1) EP2922824A1 (de)
HU (1) HU230149B1 (de)
WO (1) WO2014080341A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109485608B (zh) * 2018-12-24 2020-09-22 大连大学 一种4,6-二氯-5-氟-2-氨基嘧啶工业化生产方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008705A1 (en) * 1990-11-14 1992-05-29 The Upjohn Company 5-fluoro-2,4,6-pyrimidinetriamine compounds
US5958930A (en) * 1991-04-08 1999-09-28 Duquesne University Of The Holy Ghost Pyrrolo pyrimidine and furo pyrimidine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2014080341A1 *

Also Published As

Publication number Publication date
HU230149B1 (hu) 2015-09-28
HUP1200674A2 (en) 2014-05-28
WO2014080341A1 (en) 2014-05-30

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