EP1529036A1 - Procede de production de 4-amino-5,6-dimethoxypyrimidine cristalline de grande purete - Google Patents

Procede de production de 4-amino-5,6-dimethoxypyrimidine cristalline de grande purete

Info

Publication number
EP1529036A1
EP1529036A1 EP03763777A EP03763777A EP1529036A1 EP 1529036 A1 EP1529036 A1 EP 1529036A1 EP 03763777 A EP03763777 A EP 03763777A EP 03763777 A EP03763777 A EP 03763777A EP 1529036 A1 EP1529036 A1 EP 1529036A1
Authority
EP
European Patent Office
Prior art keywords
amino
dimethoxypyrimidine
methyl ether
butyl methyl
methoxypyrimidine
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Withdrawn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
EP03763777A
Other languages
German (de)
English (en)
Inventor
Thomas GÜTHNER
Doris Krammer
Bernd Braml
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.)
Evonik Operations GmbH
Original Assignee
Degussa 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 Degussa GmbH filed Critical Degussa GmbH
Publication of EP1529036A1 publication Critical patent/EP1529036A1/fr
Withdrawn legal-status Critical Current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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms

Definitions

  • the present invention relates to a process for the preparation of high-purity, crystalline 4-amino-5,6-dimethoxypyrimidine, starting from 4-amino-6-chloro-5-methoxypyrimidine.
  • 4-Amino-5,6-dimethoxypyrimidine is a valuable intermediate in the production of active pharmaceutical ingredients, in particular bactericidal sulfadoxine (cf. H. Bretschneider et. Al., Monthly Chem. 96 (1965) 1661).
  • 4-Amino-6-chloro-5-methoxypyrimidine to 4-amino-5,6-dimethoxypyrimidine are mentioned, for example: a solution of sodium metal in methanol, a solution of sodium methylate in methanol or a solution of sodium hydroxide in methanol.
  • a solution of sodium metal in methanol a solution of sodium methylate in methanol or a solution of sodium hydroxide in methanol.
  • an alkali hydroxide in methanolic solution is to be regarded as preferred.
  • the reaction mixture obtained is freed from methanol, taken up in water and extracted with an organic solvent.
  • dichloromethane is a highly environmentally hazardous substance and may only be handled in specially equipped systems.
  • Diethyl ether and diisopropyl ether are solvents which, due to their slight peroxide formation after exposure to oxygen, have often led to accidents and should therefore be avoided.
  • Ethyl acetate is a relatively safe solvent. When extracting from the basic, e.g. However, NaOH-containing reaction solution hydrolyzes it to ethanol and acetate and prevents trouble-free phase separation, which is why its use also poses problems.
  • a particularly pure 4-amino-5,6-dimethoxypyrimidine is desired for further processing to the pharmaceutical active ingredient sulfadoxine.
  • the processes described provide clearly varying, in some cases significantly lower melting points.
  • the process according to CH 405 322 yields a 4-amino-5,6-dimethoxypyrimidine with a melting point of 92 to 93 ° C., purified by recrystallization from diisopropyl ether and subsequent two-time sublimation. Before the sublimations, the melting point is 88 to 89 ° C.
  • a product with a melting range of 86 to 91 ° C was obtained from ethyl acetate, which melted after sublimation at 89 to 91 ° C, after sublimation again at 90 to 92 ° C.
  • VA Zasosov obtained a product with a melting point of 85 to 88 ° C from dichloromethane.
  • the present invention was therefore based on the object of a technically and economically feasible process for the preparation, isolation and purification of 4-amino-5,6-dimethoxypyrimidine by a) reacting 4-amino-6-chloro-5-methoxypyrimidine with methanol and to develop a base that does not have the disadvantages of the prior art, but rather can deliver high-purity 4-amino-5,6-dimethoxypyrimidine in conventional apparatus and without additional effort.
  • the object of the invention was achieved in that b) the methanolic solvent was completely or partially replaced by water, c) the aqueous or aqueous-methanolic solution was extracted with t-butyl methyl ether and d) the extracted product was crystallized from t-butyl methyl ether.
  • t-butyl methyl ether is capable of delivering 4-amino-5,6-dimethoxypyrimidine, which is extremely pure compared to the prior art, in high yield, the process being comparatively simple to carry out industrially.
  • the product is obtained in crystalline form and can be separated off or processed very well (for example by filtration).
  • 4-amino-6-chloro-5-methoxypyrimidine is assumed, which, for example, according to known method from 4,6-dichloro-5-methoxypyrimidine is obtained by reaction with ammonia.
  • the starting material can be used in dried form or as a moist, in particular water-moist, filter cake.
  • the 4-amino-6-chloro-5-methoxypyrimidine is dissolved or suspended in methanol and reacted with the addition of a base.
  • an alkali methylate or alkali hydroxide is used as the base.
  • Preferred bases are e.g. Sodium methylate, potassium methylate, solid sodium hydroxide, solid potassium hydroxide, aqueous sodium hydroxide solution in the concentration range from 25 to 70% by weight, preferably from 30 to 65% by weight, more preferably from 45 to 55% by weight, and / or aqueous potassium hydroxide solution Concentration range 20 to 60 wt .-%, preferably from 30 to 55 wt .-%, more preferably from 40 to 50 wt .-%.
  • Aqueous sodium hydroxide solution is particularly preferred, in particular as a 50% by weight solution.
  • the reaction can take place under increased or reduced pressure.
  • Increased pressure means that the pressure is greater than atmospheric pressure, e.g. can be increased by 0.5 bar to 10 bar, preferably by 1 to 8 bar, more preferably 2 to 5 bar, in relation to atmospheric pressure.
  • Reduced pressure means that the pressure is lower than atmospheric pressure.
  • the pressure is e.g. from 0.9 bar to 0.2 bar, preferably from 0.7 to 0.3 bar, more preferably from 0.5 to 0.4 bar.
  • the reaction is particularly preferably carried out at atmospheric pressure.
  • the reaction temperature in step a) can be 20 to 100 ° C, preferably 40 to 80 ° C, more preferably 50 to 75 ° C, particularly preferably 65 to 70 ° C. It is preferred that the reaction be under Boiling conditions at atmospheric pressure and a resulting temperature of 65 to 70 ° C is carried out.
  • 1.0 to 5.0 mol of base can be used per 1 mol of 4-amino-6-chloro-5-methoxypyrimidine.
  • the amount of base should be minimized for economic reasons, on the other hand, an excess of base with by-products (e.g. hydroxypyrimidines) can keep in solution. It is particularly preferred to work with a base amount of 1.05 to 2.0 moles.
  • Methanol is preferably used as a solvent and reactant, the amount being mainly determined by the stirrability.
  • 300 to 800 ml of methanol are used per 1 mol of 4-amino-6-chloro-5-methoxypyrimidine, more preferably 400 to 650 ml of methanol are used.
  • the methanolic solvent is completely or partially replaced by water in stage b). This can be done by completely distilling off or evaporating off the methanol and redissolving the product in water or by adding water before or during the distillation. A volume of water corresponding to the volume of methanol removed can be added. However, more or less water can be added than the volume of methanol removed.
  • the mixture preferably contains less than or equal to 10% by weight of methanol, more preferably less than or equal to 8% by weight, particularly preferably less than or equal to 5% by weight of methanol.
  • methanol preferably less than or equal to 8% by weight
  • 5% preferably less than or equal to 5% by weight of methanol.
  • the mixture obtained is extracted in step c) with t-butyl methyl ether.
  • This is a comparatively safe solvent with an extremely low tendency to form peroxides, low toxicity and a high ignition temperature.
  • the extraction is carried out at a preferred temperature of 10 to 55 ° C., in particular 25 to 50 ° C., with an amount sufficient to dissolve the 4-amino-5,6-dimethoxypyrimidine present, preferably 200 to 2000 ml, more preferably 250 ml to 1,500 ml, in particular 300 to 800 ml of t-butyl methyl ether per mole of 4-amino-6-chloro-5-methoxypyrimidine used.
  • the aqueous phase is extracted 1 to 5 times, preferably 2 to 4 times, with further t-butyl methyl ether to increase the yield, the amount of solvent used depending on the batch size.
  • the amount of solvent used depending on the batch size.
  • 4-amino-6-chloro-5-methoxypyrimidine used e.g. 50 ml to 1500 ml, preferably 1 50 ml to 1250 ml, more preferably 250 ml to 1000 ml and even more preferably 500 to 750 ml of t-butyl methyl ether.
  • the combined organic phases can optionally be treated with activated carbon, which is preferably separated off in a subsequent filtration.
  • the extracted product is crystallized from t-butyl methyl ether.
  • the combined organic phases can be partially evaporated, so that preferably 50 to per mole of 4-amino-6-chloro-5-methoxypyrimidine used 300 ml, more preferably 100 to 200 ml, in particular 50 to 100 ml of t-butyl methyl ether remain in the residue.
  • the precipitated 4-amino-5,6-dimethoxypyrimidine is filtered off and dried.
  • the yields are in particular ⁇ 93%, more preferably> 95%, even more preferably> 98%.
  • the contents, determined by gas chromatography, are> 99.5%, in particular ⁇ 99.7%, more preferably> 99.8% and can be up to 99.9 to 99.99% or more.
  • This highly pure product enables better product quality when processed into active pharmaceutical ingredients, especially sulfadoxine, and prevents the formation of unwanted by-products.

Landscapes

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

Abstract

L'invention concerne un procédé permettant de produire 4-amino-5,6-diméthoxypyrimidine cristalline de grande pureté, par a) réaction de 4-amino-6-chloro-5-méthoxypyrimidine avec du méthanol et une base, dans une plage de températures comprise entre 20 et 100 °C ; b) le solvant méthanolique est remplacé en totalité ou en partie par de l'eau ; c) la solution aqueuse ou aqueuse-méthanolique est extraite avec du t-butylméthyléther et d) le produit extrait est cristallisé hors du t-butylméthyléther. Etonnamment, il a été démontré qu'il est possible d'obtenir des rendements élevés de 4-amino-5,6-diméthoxypyrimidine cristalline et extrêmement pure, en utilisant du t-butylméthyléther comme agent d'extraction. Ledit procédé est aisé à mettre en oeuvre sur le plan technique, comparativement aux autres procédés en vigueur.
EP03763777A 2002-07-12 2003-07-09 Procede de production de 4-amino-5,6-dimethoxypyrimidine cristalline de grande purete Withdrawn EP1529036A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10231496 2002-07-12
DE2002131496 DE10231496B4 (de) 2002-07-12 2002-07-12 Verfahren zur Herstellung von hochreinem, kristallinem 4-Amino-5,6-dimethoxypyrimidin
PCT/EP2003/007446 WO2004007466A1 (fr) 2002-07-12 2003-07-09 Procede de production de 4-amino-5,6-dimethoxypyrimidine cristalline de grande purete

Publications (1)

Publication Number Publication Date
EP1529036A1 true EP1529036A1 (fr) 2005-05-11

Family

ID=30009918

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03763777A Withdrawn EP1529036A1 (fr) 2002-07-12 2003-07-09 Procede de production de 4-amino-5,6-dimethoxypyrimidine cristalline de grande purete

Country Status (4)

Country Link
EP (1) EP1529036A1 (fr)
AU (1) AU2003250930A1 (fr)
DE (1) DE10231496B4 (fr)
WO (1) WO2004007466A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709108B (zh) * 2014-01-03 2016-05-11 湖北瑞锶科技有限公司 一种合成2-氨基-4,6-二甲氧基嘧啶的生产方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH405322A (de) * 1961-03-17 1966-01-15 Hoffmann La Roche Verfahren zur Herstellung von neuen Sulfonamiden der Pyrimidinreihe

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2004007466A1 *

Also Published As

Publication number Publication date
DE10231496B4 (de) 2005-05-12
AU2003250930A1 (en) 2004-02-02
DE10231496A1 (de) 2004-02-05
WO2004007466A1 (fr) 2004-01-22

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