WO2004037795A1 - Verfahren zur herstellung von 2-amino-4-chlor-6-alkoxypyrimidinen - Google Patents
Verfahren zur herstellung von 2-amino-4-chlor-6-alkoxypyrimidinen Download PDFInfo
- Publication number
- WO2004037795A1 WO2004037795A1 PCT/EP2003/011844 EP0311844W WO2004037795A1 WO 2004037795 A1 WO2004037795 A1 WO 2004037795A1 EP 0311844 W EP0311844 W EP 0311844W WO 2004037795 A1 WO2004037795 A1 WO 2004037795A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- solvent
- mixture
- chloro
- reaction
- Prior art date
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
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Definitions
- the present invention relates to a process for the preparation of 2-amino-4-chloro-6-alkoxypyrimidines.
- ACMP 2-Amino-4-chloro-6-methoxypyrimidine
- ACMP is also used as an intermediate in active pharmaceutical ingredients; so z. B. in diabetes (cf. WO 01/36 416) or anti-cancer drugs (Zhenghou Daxue, Ziran Kexueban (2000), 32 (2), 87-88).
- 2-amino-4-chloro-6-ethoxypyrimidine has been described, for example, in connection with the synthesis of herbicides (EP-A 101 308, JP 62111982, Huaxue Shiji (1999) 21 (2), 73-75) and 2 -Amino-4-chloro-6-n-propoxypyrimidine is, for example used as an intermediate in the synthesis of active pharmaceutical ingredients (J. Chem. Med. (1986 19 (5) 676-81).
- ACMP can also be prepared starting from the N-cyano-cyanoacetimido methyl ester by reaction with a hydrogen halide (cf. JP 01016770). However, the yield in this process is only 60%.
- the object of the present invention was therefore to provide a process by which 2-amino-4-chloro-6-alkoxypyrimidines can be reacted with an alkali metal alcoholate or a Mixture of alkali metal hydroxides and an alcohol can be prepared without disturbing amounts of 2-amino-4,6-dichloropyrimidine remaining as a starting material in the product.
- the ADCP and the corresponding alkali alcoholate are used in a preferred molar ratio of 1: 1 to 1.5 and particularly preferably 1: 1.05 to 1.10.
- Solvent (mixture) carried out, but it is by no means limited to special solvents within this framework. From the series of polar aprotic solvents, those have proven to be particularly suitable which are selected from the group of ketones, amides or nitriles and acetone, methyl ethyl ketone, dimethylimidazolidinone, cyclohexanone, dimethylformamide, N-methylpyrrolidone, acetonitrile and / or their are particularly preferred Mixtures used. Acetone can be regarded as a particularly preferred solvent due to its well-known low toxicity and the simple work-up of the mother liquor formed.
- reaction at temperatures between 5 and 60 ° C and particularly preferably between 15 and 40 ° C results in a particularly good selectivity of the process according to the invention.
- the selectivity of the reaction necessary for the product is achieved above all by reaction at low temperatures below about 20 ° C. and a limitation of the alcoholate or the mixture of alkali metal hydroxide / alcohol.
- 2-Amino-4,6-dichloropyrimidine is generally initially introduced into the solvent and then the alcoholate, for example methylate, or the alkali metal hydroxide and the alcohol, for example methanol, are metered in.
- the invention provides for the mixture to be heated to a higher temperature after the addition of the reactants, particularly preferably to temperatures between 20 and 60 ° C. and in particular to temperatures between 25 and 45 ° C. If necessary, the reaction can thus be completed after the addition and after-reaction time have ended.
- the distillate can be recycled without any problems, which advantageously means that the amount of waste generated in the process according to the invention is extremely low.
- the product is then precipitated according to the present invention by adding water.
- the water can be added in the form of several portions during the distillation or after the distillation step, which the invention also takes into account.
- the procedure of adding in portions during the distillation is preferred, since more solvent can be distilled off in this way and higher yields can be achieved as a result.
- the salt formed in the reaction can either be separated off, for example by filtration from the polar aprotic solvent (acetone) before adding water, and / or the salt can be dissolved in the mother liquor by adding water, which is preferred according to the invention.
- the product itself is usually isolated by filtration and then dried in vacuo after washing with water.
- a cleaning step with activated carbon can be carried out according to the invention.
- the addition takes place after the reaction and preferably before and / or during the distillation and it is preferably additionally stirred for about another hour under the conditions of the after-reaction, that is to say for example at temperatures between 20 and 60 ° C.
- the activated carbon is then filtered off together with the salt even before the distillation, which advantageously means that all impurities from the raw material, in particular colored compounds or other disruptive by-products, e.g. B.
- 2-amino-4-chloro-6-alkoxypyrimidines and in particular the ACMP can be obtained in a particularly economical and environmentally friendly manner in high yields and with a very pronounced purity.
- the present invention relates to a process for the preparation of 2-amino-4-chloro-6-alkoxypyrimidines by reacting the 2-amino-4,6-dichloropyrimidine with an alkali metal alcoholate or a mixture of alkali metal hydroxides and an alcohol, in which the reaction in a polar aprotic solvent (mixture) is carried out, then the solvent is distilled off to> 30% and the product is precipitated by adding water during or after the distillation.
- a polar aprotic solvent mixture
- Processes in which acetone, in particular, is used as the polar aprotic solvent and which can be carried out at temperatures between 5 and 60 ° C. can be 2-amino-4-chloro-6-alkoxypyrimidines and especially 2-amino-4-chlorine -6-Methoxypyrimidine in a particularly economical and environmentally friendly manner in high yields and at the same time very distinctive purity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03775230A EP1554255A1 (de) | 2002-10-26 | 2003-10-24 | Verfahren zur herstellung von 2-amino-4-chlor-6-alkoxypyrimidinen |
JP2004545989A JP2006512305A (ja) | 2002-10-26 | 2003-10-24 | 2−アミノ−4−クロロ−6−アルコキシピリミジンの製造方法 |
US10/528,959 US20060035913A1 (en) | 2002-10-26 | 2003-10-24 | Method for the production of 2-amino-4-chloro-6-alkoxypyrimidines |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10249946A DE10249946B4 (de) | 2002-10-26 | 2002-10-26 | Verfahren zur Herstellung von 2-Amino-4-chlor-6-alkoxypyrimidinen |
DE10249946.2 | 2002-10-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004037795A1 true WO2004037795A1 (de) | 2004-05-06 |
Family
ID=32114871
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/011844 WO2004037795A1 (de) | 2002-10-26 | 2003-10-24 | Verfahren zur herstellung von 2-amino-4-chlor-6-alkoxypyrimidinen |
Country Status (5)
Country | Link |
---|---|
US (1) | US20060035913A1 (de) |
EP (1) | EP1554255A1 (de) |
JP (1) | JP2006512305A (de) |
DE (1) | DE10249946B4 (de) |
WO (1) | WO2004037795A1 (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1873151A1 (de) * | 2006-06-26 | 2008-01-02 | Chemagis Ltd. | Verbessertes Verfahren zur Herstellung von Moxonidine |
DE102012215896A1 (de) | 2012-09-07 | 2014-03-13 | Wörwag Pharma GmbH & Co.KG | Moxonidinsynthese mit Hilfe organischer Basen |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603651A (zh) * | 2012-02-27 | 2012-07-25 | 安徽丰乐农化有限责任公司 | 一种高纯农药中间体的合成新工艺 |
CN105294572A (zh) * | 2015-10-13 | 2016-02-03 | 安徽泓德化工技术有限公司 | 一甲氧基嘧啶胺的制备方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4199583A (en) * | 1970-07-13 | 1980-04-22 | The Upjohn Company | Antifungal method, formulations and compounds |
-
2002
- 2002-10-26 DE DE10249946A patent/DE10249946B4/de not_active Expired - Fee Related
-
2003
- 2003-10-24 EP EP03775230A patent/EP1554255A1/de not_active Withdrawn
- 2003-10-24 WO PCT/EP2003/011844 patent/WO2004037795A1/de not_active Application Discontinuation
- 2003-10-24 JP JP2004545989A patent/JP2006512305A/ja active Pending
- 2003-10-24 US US10/528,959 patent/US20060035913A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
---|
BOON W R: "PTERIDINES. PART IV. DERIVATIVES OF 2:4-DIAMINOPTERIDINE AND RELATED COMPOUNDS", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY. LETCHWORTH, GB, 1957, pages 2146 - 2158, XP001153711, ISSN: 0368-1769 * |
TRANTOLO ET AL: "Inhibitors of Bacillus subtilis DNA Polymerase III. Influence of Modifications in the Pyrimidine Ring of Anilino- and (Benzylamino)pyrimidines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 5, 1986, pages 676 - 681, XP002269094 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1873151A1 (de) * | 2006-06-26 | 2008-01-02 | Chemagis Ltd. | Verbessertes Verfahren zur Herstellung von Moxonidine |
EP1982983A1 (de) * | 2006-06-26 | 2008-10-22 | Chemagis Ltd. | Verbessertes Verfahren zur Herstellung von Moxonidin |
DE102012215896A1 (de) | 2012-09-07 | 2014-03-13 | Wörwag Pharma GmbH & Co.KG | Moxonidinsynthese mit Hilfe organischer Basen |
Also Published As
Publication number | Publication date |
---|---|
US20060035913A1 (en) | 2006-02-16 |
JP2006512305A (ja) | 2006-04-13 |
DE10249946B4 (de) | 2005-06-23 |
DE10249946A1 (de) | 2004-05-19 |
EP1554255A1 (de) | 2005-07-20 |
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