DE3319843A1 - Process for the preparation of pyrimidines from nitrile and alkynes - Google Patents
Process for the preparation of pyrimidines from nitrile and alkynesInfo
- Publication number
- DE3319843A1 DE3319843A1 DE19833319843 DE3319843A DE3319843A1 DE 3319843 A1 DE3319843 A1 DE 3319843A1 DE 19833319843 DE19833319843 DE 19833319843 DE 3319843 A DE3319843 A DE 3319843A DE 3319843 A1 DE3319843 A1 DE 3319843A1
- Authority
- DE
- Germany
- Prior art keywords
- nitrile
- pyrimidines
- preparation
- alkynes
- alkyne
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
Abstract
Description
VERFAHREN ZUR HERSTELLUNG VONMETHOD FOR MANUFACTURING
PYRIMIDINEN AUS NITRILEN UND ALKINEN Beschreibung Die Erfindung betrifft ein grundsätzlich neues Verfahren zur Herstellung von Pyrimidinen aus einfachen Ausgangsstoffen, bei milden Arbeitsbedingungen und guten Ausbeuten. PYRIMIDINES MADE FROM NITRILES AND ALKINES description The invention relates to a fundamentally new process for the preparation of pyrimidines from simple raw materials, with mild working conditions and good yields.
Neben den klassischen Pyrimidinsynthesen ist zwar u.a. von Kröhnke et al, Chem. Ber. 97 (1964).1163 schon eine Arbeitsweise beschrieben, unter milden Bedingungen in relativ guter Ausbeute Pyrimidine herzustellen, allerdings ist der präparative Aufwand erheblich und die Ausgangsverbindungen teilweise nur unter schwierigen Bedingungen herstellbar.In addition to the classic pyrimidine syntheses, von Kröhnke, among others et al, Chem. Ber. 97 (1964) .1163 already described a working method under mild Conditions to produce pyrimidines in relatively good yield, however, is the The preparative effort is considerable and the starting compounds are sometimes only difficult Conditions producible.
Das vorliegende Verfahren gemäß den Ansprüchen 1 bis 4 beschreitet einen prinzipiell anderen Weg und beruht auf einer Cocylotrimerisierung, der möglicherweise das folgende Reaktionsschema zugrunde liegt. The present process according to claims 1 to 4 takes a fundamentally different route and is based on a cocylotrimerization, which is possibly based on the following reaction scheme.
In den Formeln haben R1, R2 und R3 die im Patentanspruch 1 definierte Bedeutung. Die in dem erfindungsgemäßen Verfahren eingesetzte Phosphorsäure liefert die Protonen für den ersten Schritt der Reaktion. Es wird vermutet, daß der BF3-Katalysator eine Destabilisierung der ON-Bindung im Nitril bewirkt und damit die weiteren Reaktionsschritte bis zum Endprodukt erleichtert. Das Nitril dient auch als Lösungsmittel für die Umsetzung.In the formulas, R1, R2 and R3 have those defined in claim 1 Meaning. The phosphoric acid used in the process according to the invention provides the protons for the first step of the reaction. It is believed that the BF3 catalyst causes a destabilization of the ON bond in the nitrile and thus the further reaction steps facilitated to the end product. The nitrile also acts as a solvent for that Implementation.
Im nachstehenden sind die Grundtypen und einige ausgewählte Verbindungsklassen, wie sie bevorzugt im beanspruchten Verfahren eingesetzt werden, zusammengestellt, ohne daß damit eine Beschränkung auf diese Formeln gegeben ist.Below are the basic types and some selected compound classes, as they are preferably used in the claimed process, compiled, without this being restricted to these formulas.
Erfindungsgemäß einzusetzende Nitrile der allgemeinen Formel (2) können sein: mit RI als geradkettiger oder verzweigter Alkylrest, z.B. Methyl, Ethyl, iso-Propyl, n-Propyl, tert-Butyl usw. oder ein cycloaliphatischer Rest, z.B. Cyclopentyl, Cyclohexyl oder ein Phenylrest bzw. ein kernsubstituierter Phenylrest, wobei der Substituent in ortho-, meta- oder para-Stellung stehen kann und ein C1-C5-Alkyl ist, z.B. Nitriles of the general formula (2) to be used according to the invention can be: with RI as a straight-chain or branched alkyl radical, e.g. methyl, ethyl, iso-propyl, n-propyl, tert-butyl, etc. or a cycloaliphatic radical, e.g. cyclopentyl, cyclohexyl or a phenyl radical or a ring-substituted phenyl radical, the substituent in ortho- , meta- or para-position and is a C1-C5-alkyl, for example
Selbstverständlich können in der Formel (4) die Methylgruppen auch durch C2-C5-Alkylgruppen und/oder aromatische Reste ersetzt werden, jedoch enthält die Struktur nicht mehr als 18 C-Atome.Of course, the methyl groups in formula (4) can also be replaced by C2-C5-alkyl groups and / or aromatic radicals, but contains the structure no more than 18 carbon atoms.
Besonders geeignet sind die aromatischen Nitrile vom Typ der Formol R mit R1, RII Wasserstoff oder C1-C5-Alkyl, wie Methyl, Ethyl, Propyl, iso-Butyl, n-Pentyl usw. oder auch -CH2-C6H5.The aromatic nitriles of the formula R type are particularly suitable with R1, RII hydrogen or C1-C5-alkyl, such as methyl, ethyl, propyl, iso-butyl, n-pentyl, etc. or also -CH2-C6H5.
RI und RII können gleich oder verschieden sein, bevorzugt sind z.B. RI and RII can be identical or different, for example, are preferred
Des weiteren sind im erfindungsgemäßen Verfahren auch Nitrile vom Typ der Struktur (7) gut geeignet: mit RI wie in Formel(6).Furthermore, nitriles of the structure (7) type are also very suitable in the process according to the invention: with RI as in formula (6).
Allgemein sind alle Nitrile geeignet, welche in 6-Position kein Wasserstoffatom aufweisen und bei Reaktionstemperatur als Lösungsmittel für das Alkin wirken können.In general, all nitriles are suitable which do not have a hydrogen atom in the 6-position have and can act as a solvent for the alkyne at the reaction temperature.
Für die Herstellung der Pyrimidine der Formel (1) ist neben den Nitrilen auch ein Alkin der Formel (3) erforderlich (siehe auch Anspruch 1).For the preparation of the pyrimidines of the formula (1) is next to the Nitriles an alkyne of the formula (3) is also required (see also claim 1).
Insbesondere haben sich folgende Alkine als besonders gut geeignet in dem beanspruchten Verfahren erwiesen: (8) CH3 - C=C- R1 mit RI = Wasserstoff, C1-C5-Alkyl, wie Methyl, Ethyl, Propyl, iso-Propyl, n-Butyl, tert-Butyl und Pentyl, aromatische Strukturen vom Typ wobei R11 Wasserstoff oder ein Alkyl wie R1 sein kann. Es kann z.T. von Vorteil sein, die CH3-Gruppe in (8) durch Wasserstoff zu ersetzen.In particular, the following alkynes have proven to be particularly suitable in the claimed process: (8) CH3 - C = C - R1 with RI = hydrogen, C1-C5-alkyl, such as methyl, ethyl, propyl, iso-propyl, n-butyl , tert-butyl and pentyl, aromatic structures of the type where R11 can be hydrogen or an alkyl such as R1. In some cases it can be advantageous to replace the CH3 group in (8) with hydrogen.
Des weiteren eignen sich auch die aromatischen Alkine oder Alkine mit heterocyclischen Substituenten, wie mit RI und RII für Wasserstoff oder C1-C5-Alkyl. RI und RII können gleich oder verschieden se-in; oder kondensierte Ringsysteme vom Typ mit R1 und R11 die gleiche Bedeutung wie in Formel (9) bzw. (10), ganz bevorzugt oder Wasserstoff und/oder Methyl.The aromatic alkynes or alkynes with heterocyclic substituents, such as with RI and RII for hydrogen or C1-C5-alkyl. RI and RII can be identical or different; or fused ring systems of the type where R1 and R11 have the same meaning as in formula (9) or (10), very preferably or hydrogen and / or methyl.
Eine weitere wichtige Klasse von Verbindungen sind die Cyclischen Alkine vom Typ worin RIII eine C6-C16-Alkylenkette ist, insbesondere Cyclooctin sein kann, jedoch auch Cyclodecin oder Cyclododecin.Another important class of compounds are the cyclic alkynes of the type wherein RIII is a C6-C16 alkylene chain, in particular it can be cyclooctyne, but also cyclodecine or cyclododecine.
Die Reaktion läßt sich problemlos bei Temperaturen zwischen OOC bis 400C durchführen. Oberhalb von 400C sinkt die Ausbeute an Pyrimidinen rasch ab, unterhalb OOC sind viele Nitrile fest bzw.The reaction can be carried out without problems at temperatures between OOC to Perform 400C. Above 400C the yield of pyrimidines drops rapidly, below OOC, many nitriles are solid or
die Reaktionsgeschwindigkeit zu gering. Da die Nitrile im vorliegenden Verfahren im großen Überschuß vorhanden sind, ist davon auszugehen, daß bei erhöhter Temperatur als Konkurrenzreaktion zu der Cocylotrimerisierung von 2 Molen Nitril mit 1 Mol Alkin eine Cyclotrimerisierung des Nitrils stattfindet, so daß überwiegend 1,3,5-Triazin entsteht. Des weiteren kann bei noch höherer Temperatur als Konkurrenzreaktion eine Hydratisierung der Substrate zu Ketonen bzw. Säureamiden auftreten.the reaction speed is too slow. Since the nitriles in the present Process are present in large excess, it can be assumed that with increased Temperature as a competitive reaction to the cocylotrimerization of 2 moles of nitrile with 1 mole of alkyne a cyclotrimerization of the nitrile takes place, so that predominantly 1,3,5-triazine is formed. Furthermore, at an even higher temperature, as a competitive reaction hydration of the substrates to ketones or acid amides occur.
Die Verwendung der durch das vorliegende Verfahren hergestellte Pyrimidine ist allgemein bekannt, z.B. als Arznei- bzw. Pflanzenschutzmittel oder in Flüssigkristallen.The use of the pyrimidines produced by the present process is well known, e.g. as a pharmaceutical or pesticide or in liquid crystals.
Beispiele 1 bis 17 Allgemeine Darstellungsmethode von (1) aus (2) und (3) Zum Nitril (300 mmol) tropft man unter Eiskühlung und gutem Rühren den Katalysatorb) (30 g); maximale Innentemperatur 200C.Examples 1 to 17 General representation method from (1) from (2) and (3) The catalyst is added dropwise to the nitrile (300 mmol) while cooling with ice and stirring well b) (30 g); maximum internal temperature 200C.
Zu dieser Mischung läßt man in Nitril (100 mmol) gelöstes Alkin (40 mmol) tropfen (30 min). Man läßt das gelb-braune Gemisch noch 30 Minuten bei 20"C rühren. Dann wird mit Natriumchloridlösung (100 ml) versetzt, mit Toluol (3 x 70 ml) extrahiert, mit Natriumcarbonatlösung neutralisiert und über Magnesiumsulfat getrocknet.Alkyne (40%) dissolved in nitrile (100 mmol) is added to this mixture mmol) drop (30 min). The yellow-brown mixture is left at 20 ° C. for a further 30 minutes stir. Sodium chloride solution (100 ml) is then added, and toluene (3 × 70 ml), neutralized with sodium carbonate solution and over magnesium sulfate dried.
Nach Abzug des Toluols destilliert man überschüssiges Nitril im Vakuum (0,1 Torr) ab, versetzt den Rückstand mit Ethanol (50 -80 ml) und läßt kurz aufkochen. Beim Abkühlen im Eisbad erhält man das Pyrimidin als farblosen Feststoff, der durch Umkristallisieren aus Ethanol kristallin anfällt (Nitrile, Alkine und Ausbeuten siehe Tabelle).After the toluene has been removed, excess nitrile is distilled off in vacuo (0.1 Torr), the residue is mixed with ethanol (50-80 ml) and allowed to boil briefly. When cooling in an ice bath, the pyrimidine is obtained as a colorless solid, which through Recrystallization from ethanol is obtained in crystalline form (nitriles, alkynes and yields see table).
a) Im Falle von 4-Methylbenzonitril (F = 26 - 28au) tropft man langsam bei 25 - 30°C zu.a) In the case of 4-methylbenzonitrile (F = 26-28au) one drips slowly at 25 - 30 ° C.
b) Zur Herstellung des Katakysators leitet man in 85 %ige Phosphorsäure (100 g) bis zur Sättigung Bortriflurid (etwa 105 g) ein.b) To produce the catalyst, it is passed into 85% phosphoric acid (100 g) boron trifluride (approximately 105 g) to saturation.
Tabelle
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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DE19833319843 DE3319843A1 (en) | 1983-06-01 | 1983-06-01 | Process for the preparation of pyrimidines from nitrile and alkynes |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19833319843 DE3319843A1 (en) | 1983-06-01 | 1983-06-01 | Process for the preparation of pyrimidines from nitrile and alkynes |
Publications (1)
Publication Number | Publication Date |
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DE3319843A1 true DE3319843A1 (en) | 1984-12-06 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DE19833319843 Withdrawn DE3319843A1 (en) | 1983-06-01 | 1983-06-01 | Process for the preparation of pyrimidines from nitrile and alkynes |
Country Status (1)
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DE (1) | DE3319843A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4931560A (en) * | 1987-09-28 | 1990-06-05 | Ciba-Geigy Corporation | Pesticides |
US5153200A (en) * | 1987-09-28 | 1992-10-06 | Ciba-Geigy Corporation | Pesticides |
US5521189A (en) * | 1994-05-06 | 1996-05-28 | The University Of Nc At Ch | Methods of treating pneumocystis carinii pneumonia |
WO1998024782A2 (en) * | 1996-12-05 | 1998-06-11 | Amgen Inc. | Substituted pyrimidine compounds and their use |
AU733877B2 (en) * | 1996-12-05 | 2001-05-31 | Amgen, Inc. | Substituted pyrimidine compounds and their use |
US6410729B1 (en) | 1996-12-05 | 2002-06-25 | Amgen Inc. | Substituted pyrimidine compounds and methods of use |
EP1314731A2 (en) * | 1996-12-05 | 2003-05-28 | Amgen Inc. | Substituted pyrimidine compounds and their use |
JP2006510732A (en) * | 2002-10-30 | 2006-03-30 | チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド | Electroluminescent device |
JP2009531370A (en) * | 2006-03-29 | 2009-09-03 | エフ.ホフマン−ラ ロシュ アーゲー | Pyridine and pyrimidine derivatives as mGluR2 antagonists |
CN113149912A (en) * | 2021-04-01 | 2021-07-23 | 苏州久显新材料有限公司 | Cycloalkanepyrimidine derivative and preparation method and application thereof |
US11289658B2 (en) | 2002-10-30 | 2022-03-29 | Udc Ireland Limited | Electroluminescent device |
US11968893B2 (en) | 2002-10-30 | 2024-04-23 | Udc Ireland Limited | Electroluminescent device |
-
1983
- 1983-06-01 DE DE19833319843 patent/DE3319843A1/en not_active Withdrawn
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4931560A (en) * | 1987-09-28 | 1990-06-05 | Ciba-Geigy Corporation | Pesticides |
US5153200A (en) * | 1987-09-28 | 1992-10-06 | Ciba-Geigy Corporation | Pesticides |
US5521189A (en) * | 1994-05-06 | 1996-05-28 | The University Of Nc At Ch | Methods of treating pneumocystis carinii pneumonia |
US5606058A (en) * | 1994-05-06 | 1997-02-25 | The University Of North Carolina At Chapel Hill | Compounds for the treatment of pneumocystis carinii Pneumonia, Giardia Lamblia, and Cryptospordium parnum |
US5622955A (en) * | 1994-05-06 | 1997-04-22 | The University Of North Carolina At Chapel Hill | Methods of treating cryptosporidium parvum |
US5627184A (en) * | 1994-05-06 | 1997-05-06 | The University Of North Carolina At Chapel Hill | Methods of treating Giardia lamblia |
US5686456A (en) * | 1994-05-06 | 1997-11-11 | The University Of North Carolina | Methods of treating pneumocystis carinii pneumonia |
US6410729B1 (en) | 1996-12-05 | 2002-06-25 | Amgen Inc. | Substituted pyrimidine compounds and methods of use |
US6610698B2 (en) | 1996-12-05 | 2003-08-26 | Amgen, Inc. | Substituted pyrimidine compounds and methods of use |
AU733877B2 (en) * | 1996-12-05 | 2001-05-31 | Amgen, Inc. | Substituted pyrimidine compounds and their use |
WO1998024782A2 (en) * | 1996-12-05 | 1998-06-11 | Amgen Inc. | Substituted pyrimidine compounds and their use |
AU733877C (en) * | 1996-12-05 | 2003-05-08 | Amgen, Inc. | Substituted pyrimidine compounds and their use |
EP1314731A2 (en) * | 1996-12-05 | 2003-05-28 | Amgen Inc. | Substituted pyrimidine compounds and their use |
EP1314732A2 (en) * | 1996-12-05 | 2003-05-28 | Amgen Inc. | Substituted pyrimidine compounds and their use |
WO1998024782A3 (en) * | 1996-12-05 | 1998-08-27 | Amgen Inc | Substituted pyrimidine compounds and their use |
EP1314732A3 (en) * | 1996-12-05 | 2004-01-02 | Amgen Inc. | Substituted pyrimidine compounds and their use |
EP1314731A3 (en) * | 1996-12-05 | 2004-01-02 | Amgen Inc. | Substituted pyrimidine compounds and their use |
JP2006510732A (en) * | 2002-10-30 | 2006-03-30 | チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド | Electroluminescent device |
US11289658B2 (en) | 2002-10-30 | 2022-03-29 | Udc Ireland Limited | Electroluminescent device |
US11968893B2 (en) | 2002-10-30 | 2024-04-23 | Udc Ireland Limited | Electroluminescent device |
JP2009531370A (en) * | 2006-03-29 | 2009-09-03 | エフ.ホフマン−ラ ロシュ アーゲー | Pyridine and pyrimidine derivatives as mGluR2 antagonists |
CN113149912A (en) * | 2021-04-01 | 2021-07-23 | 苏州久显新材料有限公司 | Cycloalkanepyrimidine derivative and preparation method and application thereof |
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