WO1990006918A1 - A process for the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines - Google Patents
A process for the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines Download PDFInfo
- Publication number
- WO1990006918A1 WO1990006918A1 PCT/DK1989/000293 DK8900293W WO9006918A1 WO 1990006918 A1 WO1990006918 A1 WO 1990006918A1 DK 8900293 W DK8900293 W DK 8900293W WO 9006918 A1 WO9006918 A1 WO 9006918A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- alkali metal
- aralkyl
- alkyl
- formula
- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- 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 novel process for the preparation of 2,4- or 2,4,5-substit ted 6-hy- droxypyrimidines of the general formula I
- R 1 represents alkyl [preferably CH 3 , C 2 H 5 , n-C 3 H 7 , CH(CH 3 ) 2 or n-C 4 Hg] or
- R 2 represents alkyl, aryl or aralkyl [preferably CH 3 , C 2 H 5 , n-C 3 H , CH(CH 3 ) 2 , n-C 4 H 9 , C(CH 3 ) 3 , CgH 5 or CH 2 CH 2 C 6 H 5 ], and R 3 , R 7 and R 8 each independently represents hydrogen.
- R 4 represents alkyl, aryl or aralkyl [prefera ⁇ bly CH 3 , C 2 H 5 , n-C 3 H 7 , CH( ' CH 3 ) 2 , n-C 4 Hg, ' C(CH 3 )3, CgH 5 or CH 2 CgH 5 ⁇ , and
- R 5 and R 6 each independently represents hydrogen, alkyl or aralkyl [preferably H, CH 3 , C 2 H 5 , n-C 3 H 7 , CH(CH 3 ) 2 , n-C 4 H 9 , C(CH 3 ) 3 , CH 2 C 6 H 5 or CH 2 CH 2 C 5 H 5 ], with a nitrile of the general formula III R 1 -C ⁇ N III wherein R 1 is as defined above, in the presence of a base and a solvent, and then, if desired, converting the salt formed -to the free pyrimi- dine of formula I by adding an acid.
- This process can be represented by the following reaction scheme:
- the process can be described as the reaction between a 3-aminoacrylic ester or a 3-aminoacrylamide and a nitrile while splitting off an alcohol or a monia/amine, respectively.
- the reaction is general for the above-mentioned starting materials as well as for the tauto eric forms in which the starting materials may exist.
- the starting materials occur as follows: a. Ethylcyanamide as
- the reaction proceeds in the presence of a base which can be a free alkali metal or alkaline earth metal, or an alkali metal hydride, alkali metal amide, alkali metal alkoxide, alkali metal phenolate, alkali metal hydroxide, alkali metal carbonate or alkali metal carboxylate or a corresponding alkaline earth metal compound.
- a salt results, e.g., an alkali metal salt of the pyrimidine.
- the free pyrimidine may be released therefrom by treatment with an acid such as a mineral acid or an organic acid.
- a sol ⁇ vent which by way of example may be an alcohol, ether, ethylene glycol ether, ketone or carbonic ester or an aliphatic or aromatic hydrocarbon.
- the reaction generally proceeds at a temperature of between 20 C and 180 C, preferably between 80 C and 140°C.
- a number of processes for the preparation of industrially interesting pyrimidines is known as described below.
- U.S. Patent No. 4,014,879, U.S. Patent No. 4,496,728 and GB Patent No. 2,083,814 deal with the preparation of 2-isopropyl-4-methyl-6-hydroxypyrimi- dine from isobutyronitrile.
- Isobutyronitrile is converted to isopropylimino- ether by reaction with alcohol and dry hydrogen chlo ⁇ ride.
- Isopropyliminoether is converted to isopropyl- amidine by reaction with ammonia.
- Isopropylamidine is reacted with methyl acetoacetate to form 2-isopropyl- 4-methyl-6-hydroxypyrimidine.
- JP Patent Abstract No. 48/39943 describes a similar reaction from isopropylamidine and diketene
- GB Patent No. 2,027,710 describes the reaction between isopropyliminoether and diketene, followed by reaction with ammonia.
- GB Patent No. 1,182,584 deals with the prepara ⁇ tion of 2-dimethylamino-4-methyl-6-hydroxypyrimidine from dimethylguanidine and ethyl acetoacetate.
- the process of the invention differs from the processes thus known for the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines in that use is made of already known starting materials, but in a combination not previously known, and in this connec ⁇ tion it is surprising that nitriles react with, the 3- or 2,3-substituted 3-aminoacrylic acid derivatives of formula II as used according to the invention.
- nitriles react with, the 3- or 2,3-substituted 3-aminoacrylic acid derivatives of formula II as used according to the invention.
- the process of the invention differs also from the known processes in that the reaction is more general, and therefore the process of the invention is applicable for the preparation of a wide range of substituted pyrimidines, the utility of which will be known or obvious to a person skilled in the art.
- a mixture of 143 g of 2-methyl-3-aminocrotonic acid ethylester, 70 g of ethylcyanamide and 138 g of potassium carbonate in 300 ml of diethyl carbonate is heated at reflux for 6 hours.
- the reaction mixture is worked up by one of the following methods:
- the reaction mixture is neutralized with a mineral acid (e.g., dry hydrogen chloride or cone, sulphuric acid) or an organic acid (e.g. acetic acid), heated at reflux for half an hour and evaporated to dryness on a rotary evapo ⁇ rator, and then 200 ml of water is added.
- a mineral acid e.g., dry hydrogen chloride or cone, sulphuric acid
- an organic acid e.g. acetic acid
- the 2-ethylamino-4,5-dimethyl-6-hydroxypyrimi- dine formed appears as a white to pale yellow product which after drying has a purity >95% determined by HPLC.
- the 13 C NMR spectrum of the product in deuterated DMSO [Product 4] is shown.
- 2-ethylamino-4-methyl-5- n-butyl-6-hydroxypyrimidine can be prepared by using 2-n-butyl-3-aminocrotonic acid ethylester instead of 2-methyl-3-aminocrotonic acid ethylester.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK700688A DK160270C (da) | 1988-12-16 | 1988-12-16 | Fremgangsmaade til fremstilling af 2,4- eller 2,4,5-substituerede 6-hydroxypyrimidiner |
DK7006/88 | 1988-12-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1990006918A1 true WO1990006918A1 (en) | 1990-06-28 |
Family
ID=8149192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1989/000293 WO1990006918A1 (en) | 1988-12-16 | 1989-12-14 | A process for the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines |
Country Status (2)
Country | Link |
---|---|
DK (1) | DK160270C (da) |
WO (1) | WO1990006918A1 (da) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0515265B1 (fr) * | 1991-05-23 | 1997-04-16 | Roussel Uclaf | Dérivés de la pyrimidine, leur procédé de préparation, les intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant |
WO2000063183A1 (en) * | 1999-04-15 | 2000-10-26 | American Cyanamid Company | Process for the preparation of substituted pyrimidines |
US6281358B1 (en) | 1999-04-15 | 2001-08-28 | American Cyanamid Company | Process for the preparation of substituted pyrimidines |
WO2015036563A1 (de) | 2013-09-16 | 2015-03-19 | Bayer Pharma Aktiengesellschaft | Disubstituierte trifluormethylpyrimidinone und ihre verwendung als ccr2 antagonisten |
US20180030169A1 (en) * | 2016-07-29 | 2018-02-01 | Phillips 66 Company | Thermoresponsive polymers |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0271834A2 (de) * | 1986-12-16 | 1988-06-22 | Hoechst Schering AgrEvo GmbH | Verfahren zur Herstellung von Pyrimidinen |
-
1988
- 1988-12-16 DK DK700688A patent/DK160270C/da not_active IP Right Cessation
-
1989
- 1989-12-14 WO PCT/DK1989/000293 patent/WO1990006918A1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0271834A2 (de) * | 1986-12-16 | 1988-06-22 | Hoechst Schering AgrEvo GmbH | Verfahren zur Herstellung von Pyrimidinen |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0515265B1 (fr) * | 1991-05-23 | 1997-04-16 | Roussel Uclaf | Dérivés de la pyrimidine, leur procédé de préparation, les intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant |
WO2000063183A1 (en) * | 1999-04-15 | 2000-10-26 | American Cyanamid Company | Process for the preparation of substituted pyrimidines |
US6281358B1 (en) | 1999-04-15 | 2001-08-28 | American Cyanamid Company | Process for the preparation of substituted pyrimidines |
US6559307B2 (en) | 1999-04-15 | 2003-05-06 | Basf Aktiengesellschaft | Process for the preparation of substituted pyrimidines |
WO2015036563A1 (de) | 2013-09-16 | 2015-03-19 | Bayer Pharma Aktiengesellschaft | Disubstituierte trifluormethylpyrimidinone und ihre verwendung als ccr2 antagonisten |
US20180030169A1 (en) * | 2016-07-29 | 2018-02-01 | Phillips 66 Company | Thermoresponsive polymers |
Also Published As
Publication number | Publication date |
---|---|
DK700688D0 (da) | 1988-12-16 |
DK160270B (da) | 1991-02-18 |
DK160270C (da) | 1991-08-05 |
DK700688A (da) | 1990-06-17 |
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