DE1670069A1 - Process for the preparation of pyrimidines substituted in the 5-position by halogen - Google Patents

Description

Process for the preparation of halogen-substituted in the 5-position: pyrimidines It has been found that halogen-substituted pyrimidines of the formula in which Ri is hydrogen, an alkyl-e cyeloalkyl-, aralkyl- or an arylrean which is optionally substituted by substituents which are inert under the reaction conditions, X is a halogen atom and Y is the radical -Z-R2t in which Z is an oxygen or sulfur atom and R Denotes hydrogen or an alkyl, aralkyl, aryl or cycloalkyl radical which is optionally 2 substituted by halogen, nitro, alkoxy or secondary 4mino groups, for the radical wherein R 3 and R 4 are hydrogen, alkyl, cycloalkyl, aralkyl or aryl radicals and R and -R can also together form an alkylene radical 3 4 with 2 to 6 carbon atoms in which a methylene group is replaced by an oxygen or sulfur atom, by one of the groups known as 2 9The. ## NH 59 wherein R 5 is an alkyl, cycloalkyl or represents the phenyl radical may sem replaced, for the rest wherein R 29, R3 and R 4 have the abovementioned meaning, or the radical -N stands in good yields and in a simple manner as er-3.

holds if one 4,5-dihalopyrimidines of the formula wherein R 1 and X have the abovementioned meaning with a compound which has the general formula H y III, in which Y has the abovementioned meaning, optionally in the presence of a base, or with an alkali or alkaline earth metal salt of the compound HY at temperatures between 30 and 200 ° C., optionally in the presence of a solvent and, if necessary, under increased pressure. The process is preferably carried out at temperatures between 50 and 150 ° C. The process can be used for the preparation of 2-phenyl-4 -Methoxy.5-chloropyrimidine by reacting 2-phenyl-4,5-dichloropyrimidine with sodium methylet using the following reaction equation: The 4,5-dihalopyrimidines of the formula II used as starting materials are new substances. They can be easily prepared by reacting, for example, 4-hydroxy-5-halopyrimidines, which in turn can be obtained by reacting, for example, 2,3-dihaloacrylic acid ethyl ester with amidines with, for example, phosphorus oxyhalides in the presence of a tertiary amine. Preferred starting pyrimidines are those in which, in the formula II, X is chlorine, bromine or iodine and R 1 is hydrogen, an alkyl radical having 1 to 6 carbon atoms, a cycloalkyl radical having 5 to 12 carbon atoms, an aralkyl radical having 7 to 9 carbon atoms or an aryl radical with 6 to 12 carbon atoms .. Furthermore, the aryl radical can in the preferred Ausgen gspyrimidinen still by 1 to 3 uritee the reaction conditions inert substituents, such as chlorine, bromine, iodine, nitro groups, alkyl, alkoxy or alkylmerka, ptoreste with preferably 1 to 4 carbon atoms each, substituted: -be. 11 f, As starting materials of the general formula III, in which Y is acid substance means you can use alcohols. Can be used as alcohols one alkanules with e.g. 1 to 14 carbon atoms, e.g. methanol, Ethenol, isopropanol, butanol, 2-Äth # lhexanoi or tridecanolg Aralkanols with, for example, 7 to 12 carbon atoms, such as benzyl alcohol o (- or ß-phenylethanol, and cycloalkanols with e.g. 5-to 14 Carbon atoms such as cyclohexanol, cyclooctenol, cyclododecanol or use 4-methyl-cyclohexanol. You can also Use phenols as starting materials. Suitable phenols are, for example Phenol, p-nitrophenol, 2,4-dichlorophenol, 2,4,6-tribromophenol, Thymol, 3-methylphenol, hydroquinone monomethyl ether or p-di- methyl aminophenol. Furthermore you can use Mereaptene as exits - use fabrics. In this case, Y in the formula III- the . Group - S - R2 * As mereaptanes one can use alkyl mereaptanes before-- assigned with 1 to 10 carbon offset-omen, such as methyl-, iaopropyl-9, tert. Use butyl or 2-ethylhexyl mercaptan #. Farther Aralkyl mereaptanes are suitable, preferably with 7 to 12 carbon stoffatomeng, Cycloalkylmereaptene «- # preferably with 5 to 14 carbon lenstoffatomen, such as Benzylmereaptan, b # - or ß-Phenyläthylmer- ceptäng Cyclohexylmer-capten, Cyclooctylmera.epten or Cyclodo- decylmereaptene Also aromatic mereaptene, such as phenyl-, p-tolyl-, p-nitrophenyl-, p-methoxyphenyl-, 294-dichlorophenyl-, m-bromophenyl- mereapten, or p-dimethylaminothiophenol, are as, Auagangestoffe usable. In addition to the alcohols and mereaptanes mentioned, you can also use them Use alkali or alkaline earth salts as starting materials. Be-- are particularly suitable, for example. the sodium, potassium, lithium or gallium salts.

Other suitable starting materials which fall under the general formula III are ammonia, primary and secondary amines. In this case the remainder Y means the group In the amines preferably used as external substances the radicals R 3 and - H 4- W6eserst.Off, alkyl groups with 1'be- 18 carbon material atoms, Gy-cloalkyl group with 6 to 12 carbon atoms, Aralkyl radicals with 7 to 19'-j (ohlens # tof £ ä # töai # en or Phenylreäteo die also by 1 to 3 subs . tituenten "-like Vvilor, Brom-, Alkox # - Alky3.- mereapto-9 dialkylamino or alkyl groups with 1 to 4 each Carbon atoms in the alkyl groups can be substituted. Furthermore, the radicals R and, e zem -, ä m inse an alkylene rain --3 .4. with 2 to 6 carbon atoms: Wherein a methylene group des.Alkylenrestee duräh ein Beuerst-Off, - or- 8-chwe £, ötla # to-m # ede'r -be replaced by one of the -groups >, 309> 30 where R is preferably an Alkylre-ei with: r1- to 4 - Kob: leUatoff-- atoms-means. Be # spie: lawe-ii3e can m94 except Amntöniak - fol Sand er Amines converting methyl-i-.ieo-Propylq-W "a-Ethy.lhe-xyl -.,. G Cyclohexyl-v Cycloootyl- or. Cyclodgdecyla_m: # - ne, - Beazylamin, An # Iint p "Ohlor- aniline, -pT-dimethylaminoaniline.t m-79.Iiiidi4 .. DJ # zuö2th; # läXin't D4pheny14 -einin, N-Kethylaniline. Ethylenixizie # Thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperidine, 1-oxa-4-aza-2,6-dimethylcyclohexane, pyrrolidine or N-monomethylpiperazine.

Furthermore, hydrazine and substituted hydrazines can also be converted. They can be represented by the general formula III, where Y is the remainder stands. In the formula, the radicals mean. R29, R 3 and R 4 are preferably an alkyl radical having 1 to 4 carbon atoms and if R2 and R 3 are hydrogen, R 4 is a phenyl radical. Individual representatives of the hydrezines used with preference are, for example, hydrazine, methylhydrazine, symmetrically or eseymmetrically substituted methylhydrazines - they are expediently used in the form of their hydrates or as aqueous solutions, and also phenylhydrazine. Finally, StiokatQ £ fwasseratoffeäureg, preferably in the form of an alkali salt, can also be used for the conversion.

As bases, in the context of this invention, the alcoholate can be used Yhenolatep the oxydes, hydroxides and carbonates of the Alkeli- and Brdalkellmetalleg Use especially of the sodium ag, potassium, calium and barium, other suitable ones Bases are tertiary amines, such as dimethylaniling, diethylaniline, tributylamine and Pyridine. As a rule, so much is used in Basel that the two - '# - the implementation hydrogen halide which forms is neutralized. However, you can also do one Use excess base.

The process can be carried out in the presence or absence of a solvent. The solvent can be alkanols, preferably with 1 to 6 carbon atoms, such as methanol, ethanol, propanol or isobutanol, ethers such as dibutyl ether, dioxene or tetrahydrofuran, N, N-diaubstituted carboxamides, such as dimethylformamide, diethylformamide, dimethylacetamide, or N-methylpyrrolidone Use tetramethyl ether or sulfolane.

When carrying out the process, the starting materials are used in a molar ratio of 1: 1, if possible. However, an excess of the compound of the formula III can also be used. If a volatile reaction participant is reacted, it is advisable to carry out the process under increased pressure. The pressure can fluctuate within wide limits. The pressure to be used depends on the reaction temperature at which the work is to be carried out. As a rule, the use of a Pruckee of up to about 100 et is sufficient.

The new compounds which can be prepared by the process are valuable intermediates for the preparation of pharmaceuticals some of them have anti-inflammatory properties.

The anti-inflammatory effect is determined when testing (see table) using the method of CA Winter, EA Risley and GW Nuss, Prob. Lake. exp. Biol. Med. 111 (1962) "Carrageenin Induced Edema in Hind Paw of the Rat ae an Assay for Antiinflammatory Drugell, S-. 544, determined on the edema produced by carrageenin on the hind paw of rats.

In this method, an inflammatory swelling is created by injecting garrageenin into the rat's hind paw. The extent of the swelling can be prevented or weakened by anti-inflammatory substances. This attenuation is expressed as a % inhibition of the edema that occurs without pretreatment. The size of the inflammatory swelling is after completion of the rate paws cut determined by weighing. End product Oral dose edema inhibition intraperitoneal ILD 50 mg / kg % in mice mg / kg Control - - 2-phenyl-4-amino- 50 37 1,000 5-bromo-pyrimidine 150 61 2 "phenyl-4-amino- 50 34 1000 5-chloro-pyrimidine 150 65 2-l'henyl-4-hydra- 50 17 1,000 zino-5-bromo-pyri- 150 22 midin 2-phenyl-4-hydra- 50 16 750 zino-5-ohlor-pyri- 150 40 midin Comparison: Oral dose anti-edema intraperitoneal IJ) mo mg / kg % for mice mg / kg 2,3-DimethY1-1- 50 0 750 phenyl-3-pYrraz0-150 25 lin-5-on (anti pyrine) The table shows that the 2yribidine derivatives have more anti-inflammatory properties than the antipyrine while being less toxic.

The parts given in the examples are parts by weight. EXAMPLE 1 22.5 parts of 2-phenylr495-dichloropyrimidine are added to a solution of 5.4 parts of sodium dimethylate in 150 parts of methanol and the mixture is heated under reflux for 2 hours. The reaction mixture is then poured into 500 parts of water and the crystals which have separated out are filtered off. After recrystallization from ethanol, 18 parts of 2-phenyl-4-methoxy-5-chloropyrimidine from Ppe 77 00 are obtained. Example 2 22.5 parts of 2-phenyl-4 are added to a solution of 4 parts of sodium hydroxide in 150 parts of methenol. 5-dichloropyrimidine and refluxed for 2 hours.-Then, as described in Example 1 , work-up. 15 parts of 2-phenyl-4-methoxy-5-chloropyrimidine from FP- 77 0 0 are obtained.

Example 3 2.3 parts of sodium are added to a solution of 12.8 parts of p-chlorophenol in 200 parts of absolute DioxUn. After dissolving the same, 245 parts of 2-PhenY1-495-dichloropyrizidine were added and heated under reflux for 6 hours. It is then worked up as described in Example 1. This gives 18 parts of 2-phenyl-4-p-ohlorphonoxy-5-chloropyrimidine, mp. 138 0 C. In an analogous way one obtains j Example R Yield in % . Mp. 0 C 4 2-phenyl-4-ethoxy- 75 64 5-chloropyrimidine 5 2-phenyl-4-phenoxy- 68 99 5-chloropyrimidine 6 2-phenyl-4-phenthio- 81 85 5-chloropyrimidine .teia] 2iel- 7 A solution of 22.5 parts of 2-phenyl-4,5-dichloropyrimidine and 70 parts of sodium sulfide in 1000 parts of dimethylformamide is stirred for 6 hours at room temperature. Then it is poured into water and acidified with dilute hydrochloric acid. A yellow precipitate forms, which is filtered off. After recrystallization from Bensol is obtained 16 parts of 2-phenyl-4-mercapto-5-ohlorpyrimidin from Pp. 1881c.

Example 8 A mixture of 10 parts of 2-phenyl-4,5-dichloropyrimidine and 50 parts of iaobutylamine is refluxed for 4 hours. Because the excess iaobutylamine is distilled off in a water jet vacuum and the residue is fractionated. This gives 10 parts of 2-phenyl-4-isobutylamino-5-chloropyrimidine, bp .., 2 140 0 C and Pp. 44 0 C.

In an analogous way one obtains Example amine yield in % 9 2-phenyl-4-anilino- 68 106 5-chloropyrimidine 10 2-phenyl-4-piperidino- 80 88 . 5-chloropyrimidine 11 2-phenyl-4-morpholino- 85 79 5-chloropyrimidine EXAMPLE 12 2295 parts of 2-phenyl-4,5-dichloropyrimidine, 150 parts of alcohol and 30 parts of concentrated ammonia are heated to 1200 ° C. in an autoclave for 6 hours. It is then poured into water, filtered off and recrystallized from benzene. 15 parts of 2-phenyl-4-amino-5-chloropyrimidine of p. 139 ° C. are obtained. Example 13 A solution of 22.5 parts of 2-phenyl-4,5-dichloropyrimidine and 10 parts of hydrazine hydrate in 500 parts of n- Propanol is refluxed for 2 hours. After cooling, it is poured into water, the precipitate is filtered off and washed with water. After recrystallization from benzene, 16 parts of 2-phenyl-4-hydrezino-5-chloropyrimidine of p. 199 ° C. are obtained.

Example 14 22.5 parts of 2-phenyl-4,5-dichloropyrimidine and 6.5 parts of sodium azide are refluxed in 300 parts of 80% strength aqueous ethanol for 1 hour. It is then diluted with water and the reaction mixture is filtered off with suction from the precipitated crystals. After recrystallization from 20 parts of ligroin gives 2-phenyl-4-azido-5-chloropyrimidine, mp. 112 0 C.

Example 15 23.1 parts of 2-cyclohexyl-4,5-dichlorpyrimiding 150 parts of ethanol and 30 parts of concentrated ammonia are heated at 120 00 6 hours in an autoclave. It is then poured into water, filtered off and recrystallized from benzene. 16 parts of 2-cyclohexyl-4-amino-5-chloropyrimidine with a melting point of 124,000 are obtained .

Claims (1)

1. A process for the preparation of 5-substituted by halogen .Stellung Pyrimidinen'der formula wherein R 1 is hydrogen, an alkyl, cycloalkyl, aralkyl or an aryl radical optionally substituted by substituents which are inert under the reaction conditions, X is a halogen atom and Y is the radical -Z-R2, in which Z is an oxygen or sulfur atom and R 2 denotes hydrogen or an alkyl, aralkyl, aryl or cycloalkyl radical optionally substituted by halogen, nitro, alkoxy or secondary amino groups for the radical wherein R 3 and R 4 are hydrogen, alkyl, cycloalkyl-9 aralkyl or aryl radicals and R 3 and R 4 can also together form an alkylene radical having 2 to 6 carbon atoms in which a methylene group is replaced by an oxygen or sulfur atom or by a the groups > SO,> s02 or> NR 5 ' in which R 5 denotes an alkyl, cycloalkyl or phenyl radical, can be replaced "for the radical wherein R2, R3 and R 4 have the aforementioned meaning, or represents the radical -N 3 " characterized in that 4,5-dihalopyrimidines of the formula wherein R 1 and 1 have the aforementioned meaning, with a compound of the general formula H - Y wherein Y has the aforementioned meaning, optionally in the presence of a base, or with an alkali or alkaline earth metal salt of the compound NY at temperatures between 30 and 20,000, optionally in the presence of a solvent and optionally under elevated pressure. 2. 2-2henyl-4-amino-5-bromopyrimidine 3. 2-] phenyl-4-amino-5-chloropyrimidine 4. 2-phenyl-4-hydrazino-5-bromopyrimidine 5. 2- 2henyl-4-hydrazino-5-chloropyrizidine.