IL43505A - Process for bromination of nitrogen-containing heterocyclic compounds - Google Patents

Process for bromination of nitrogen-containing heterocyclic compounds

Info

Publication number
IL43505A
IL43505A IL43505A IL4350573A IL43505A IL 43505 A IL43505 A IL 43505A IL 43505 A IL43505 A IL 43505A IL 4350573 A IL4350573 A IL 4350573A IL 43505 A IL43505 A IL 43505A
Authority
IL
Israel
Prior art keywords
nitrogen
pyrimidine
hydrochloride
solvent
containing heterocyclic
Prior art date
Application number
IL43505A
Other versions
IL43505A0 (en
Original Assignee
Lilly Co Eli
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 Lilly Co Eli filed Critical Lilly Co Eli
Publication of IL43505A0 publication Critical patent/IL43505A0/en
Publication of IL43505A publication Critical patent/IL43505A/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/30Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00Halogenation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

BROMINATION I PROCESS OF NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS »¾»p»srnon man 3 in © n'si'sna i*->nn ΤΡ3Π n »30n The present invention relates to a process for brominating nitrogen-containing heterocycles which comprises reacting bromine at an elevated temperature with the hydrogen halide addition salt of the nitrogen-containing heterocycle in a solvent substantially inert to the action of bromine under the conditions of the process. A product of this process, 5-bromopyrimidine, has proven to be a valuable intermediate in the synthesis of several new agricultural products, particularly those which have interesting plant growth regulator and plant fungicidal properties.
The importance of these products led to a search for a more facile synthesis of the important intermediate, 5-bromopyrimidine.
In the prior art, Bredereck et al^ , Chem. Ber. 91, 2832 at 3848 (1958) , teach the reaction of pyrimidine hydrochloride with bromine by heating a mixture of the two in an oil bath for about 3 hours at a temperature of about 160°C, to form a solid mass, the reaction product mixture. The temperature of the oil bath was then raised to 250°C, and the 5-bromopyrimidine hydrobromide was sublimed out of the solid reaction product mixture under vacuum. The 5-bromopyrimidine hydrobromide was taken up in sodium bisulfite solution, the solution made alkaline with potassium hydroxide, and extracted with chloroform. The chloroform was distilled to leave behind pure 5-bromopyrimidine.
An alternate approach to the synthesis of 5-bromopyrimidine is also reported by Bredereck et al^. , Chem. Ber. 95, 803 at 807 and 808 (1962). 2-Bromo-l,l,3,3-tetraethoxy-propane was prepared by brominating 1,1,3,3-tetraethoxypropane in carbon tetrachloride. The 2-bromo-l,l,3, 3-tetraethoxypro- pane was then condensed with formamide, in the presence of ammonium formate and water, to give 5-bromopyrimidine.
The preparation of 4-bromoisoguinoline is taught by Gilman et al . , J. Am. Chem. Soc. 69 , 1946 (1947). Isoguino-line perbromide hydrobromide was subjected to prolonged heating, yielding a solid mass. Excess agueous sodium hydroxide solution was added to the solid mass and the liberated 4-bromoisoguinoline was recovered by steam distillation. The crude product was purified by recrystallization from petroleum ether.
The preparation of 5-bromo-4-phenylpyrimidine via a six-step synthetic process is reported by van der Plas, Rec. Trav. Chim. 84, 1101 (1965) , who stated that the direct bromination method of Bredereck et aJL. , supra , did not seem suitable for the synthesis of 5-bromo-4-phenylpyrimidine, the phenyl group being vulnerable to the attack of brominating agents.
The preparation of 3-bromoguinoline by the pyrolysis of guinoline hydrobromide perbromide at 180-200°C. is reported by Eisch, J. Org. Chem. 27, 1318 (1962) .
This invention relates to a process for brominating nitrogen-containing heterocycles . More particularly, this invention relates to a process for brominating a nitrogen-containing heterocyclic compound selected from the group consisting of pyrimidine, 4-phenylpyrimidine, guinoline, iso-guinoline, and 1,6-naphthyridine. The process comprises adding bromine at a uniform rate over a period of time to a heated mixture of the nitrogen-containing heterocycle in the form of its hydrogen halide salt and a solvent which is substantially inert to the action of bromine under the con- ditions of the reaction.
This invention makes available a process for preparing bromo-substituted, nitrogen-containing heterocycles , for example, 5-bromopyrimidine, in good yield, which process is adaptable to commercial use. The process has been found generally applicable to nitrogen-containing heterocycles.
The preparation of the bromo-substituted, nitrogen-containing heterocyclic compound is conveniently carried out utilizing a hydrogen halide addition salt of the particular nitrogen-containing heterocycle. Suitable hydrogen halide addition salts include those formed with hydrogen chloride, hydrogen bromide, or hydrogen iodide, for example, pyrimidine hydrochloride, pyrimidine hydrobromide, pyrimidine hydriodide, guinoline hydrochloride, guinoline hydrobromide, guinoline hydriodide, isoguinoline hydrobromide, isoguinoline hydrochloride, isoguinoline hydriodide, 4-phenylpyrimidine hydrobromide, 4-phenylpyrimidine hydrochloride, 4-phenylpyrimidine hydriodide, 1, 6-naphthyridine hydrobromide, 1,6-naphthyridine hydrochloride and 1,6-naphthyridine hydriodide. Of these hydrogen halide salts, the hydrogen chloride salts are preferred for use in the claimed bromination reaction.
The nitrogen-containing heterocycle hydrogen halide is suspended or dissolved in a suitable reaction solvent, the mixture heated, and bromine is added thereto. The bromine and the nitrogen-containing heterocycle hydrogen halide appear to first form a complex, which complex is soluble in the reaction solvent. The solvent selected is substantially inert to the action of bromine under the conditions of the reaction. A suitable solvent is one in which the starting nitrogen-containing heterocycle hydrogen halide addition salt is insoluble the complex formed between the bromine and the nitrogen-containing heterocycle hydrogen halide salt is quite soluble, and in which the hydrogen halide addition salt of the bromo-substituted nitrogen-containing heterocycle, the product, is substantially insoluble. Suitable solvents include thionyl chloride and phosphorus oxychloride, both of which are inorganic solvents, as well as organic solvents such as carbon tetrachloride, nitrobenzene, ortho-dichlorobenzene , chloro-benzene, ortho-nitrotoluene, benzonitrile, ortho-nitroanisole, and ortho-chloroanisole. All of these solvents are substantially inert to the action of bromine under the conditions of the novel process. While any of the above-mentioned solvents aid in obtaining better yields of the desired bromo-substi-tuted, nitrogen-containing heterocyclic compound, the organic solvents are more desirable because of their ease of handling and possibilities for recycling; Thus, the organic solvents benzonitrile, o-nitrotoluene , o-dichlorobenzene, o-nitro-anisole, and nitrobenzene are particularly helpful in obtaining better yields. Of these organic solvents, o-dichlorobenzene and nitrobenzene are preferred, with nitrobenzene being the solvent of choice.
The solvent plays an important part in this novel process. The solvent assists in controlling the temperature of the reaction mixture, and allows better mixing of the bromine and the nitrogen-containing heterocycle hydrogen halide addition salt. The solvent permits the reaction mixture to be stirred throughout the duration of the reaction, and makes it possible to obtain a higher yield of product than that obtained in the absence of a solvent. This reaction product mixture which can be stirred is in marked contrast to those described in the prior art where the reaction product mixtures set up as solid masses as the reaction proceeded.
The presence of the solvent also makes isolation of the bromo-substituted nitrogen-containing heterocycle easier. With the inert solvent present, the reaction product mixture is present in the reaction vessel as a slurry instead of a solid mass at the completion of the reaction, and the crude product can be filtered off from the solvent. This is more convenient, especially on a large-scale run, than isolating the product either by sublimation or by chiseling it out of the reaction vessel. The presence of the inert solvent thus greatly aids in making large-scale preparations feasible.
The bromination reaction is carried out by suspending the hydrogen halide addition salt of the nitrogen-containing heterocyclic compound in the inert solvent, for example, nitrobenzene, and heating the mixture to a suitable temperature. The suitable temperature varies with the heterocyclic reactant, from about 125°C. (pyrimidine) to about 200°C. (guinoline) .
The bromine is added to the heated mixture over a period of from about 30 to about 90 minutes. The addition is preferably carried out at such a rate that a smooth and controlled reaction of bromine with the nitrogen-containing heterocyclic compound is accomplished. The addition of the bromine over the period of from 30 to 90 minutes can preferably be accomplished dropwise in the laboratory. It is preferred that addition of the bromine be accomplished in equal portions at evenly spaced intervals of time, but addition of unequal portions of bromine may also be accomplished at unequal intervals of time.
As the bromine is added, hydrogen halide is evolved from the reaction mixture. The rate of evolution of the hydrogen halide is regulated by the rate of addition of the bromine. Control of the rate of evolution of the hydrogen halide is important in one aspect in that too rapid evolution of hydrogen halide may produce entrainment of the bromine being added. Such entrainment can cause loss of bromine, and cut down the yield of product, while raising the cost of production. Control of the rate of evolution of the hydrogen halide is important in another aspect in that the effluent gas from the reaction is desirably put through a scrubber to remove the hydrogen halide. Such removal is desirable in maintaining the atmosphere as free from noxious gases as possible. Thus, whether the reaction is being carried out on a laboratory scale or a commercial scale, the addition of the bromine is preferably accomplished at a rate which permits control of the rate of evolution of hydrogen halide to prevent the entrainment and loss of bromine, and which allows the efficient removal of hydrogen halide from the effluent gases produced by the reaction.
When addition of the bromine is complete, the reaction product mixture is heated for an additional period of time, about two to about six hours, to complete the reaction. Longer heating times tend to lower the yield of desired product and for that reason are to be avoided. Heating times also depend on the heterocyclic compound being brominated.
At the end of the additional heating period, the reaction product mixture is ready for work-up. The reaction product mixture is worked up by methods well known to those skilled in the art. Thus, the reaction product mixture is partially cooled, and a solvent, for example, benzene, added thereto. Other solvents which can be used include hexane, ether, toluene and xylene. The added solvent aids in diluting the inert reaction solvent and in separating the product from such inert solvent. After addition of the diluting solvent, the whole mixture is further cooled to about room temperature. The mixture is filtered to separate the solid which has precipitated upon cooling. The precipitated solid is the hydrogen halide salt of the bromo-substituted, nitrogen-containing heterocycle. The bromo-substituted, nitrogen-containing heterocyclic free base is obtained by suspending the salt in water, adjusting the pH to approximately pH 8 to 10 with strong base, and steam distilling. Suitable strong bases include sodium hydroxide, potassium hydroxide, and sodium carbonate. The product is filtered from the cooled distillate. Alternatively, the product can be recovered by extraction of the basic mixture with chloroform or ether.
The chloroform or ether extract is dried and the solvent distilled in vacuo, to yield the bromo-substituted, nitrogen-containing heterocycle.
The following examples serve to illustrate the invention, but are not to be regarded as limiting the scope thereof. Example 1 5-Bromopyrimidine A slurry of 29.0 g. (0.25 mole) of pyrimidine hydrochloride in 30 ml. of nitrobenzene, contained in a 250 ml. three-neck round-bottom flask equipped with a paddle stirrer, condenser, dropping funnel, and thermometer, was heated to about 130°C, and 44.0 g. (0.275 mole) of bromine was added dropwise through the dropping funnel over a period of 30 minutes. Heating and stirring was continued at about 130°C, for an additional two hours. At the end of that time, the reaction product mixture was cooled to about 80°C, and 150 ml. of benzene was added. The resulting slurry was filtered. The solid collected on the filter was washed with 100 ml. of benzene, and sucked dry. The dry, tan solid, which weighed 61.0 g., was placed in 200 ml. of water. The aqueous mixture was adjusted to pH 8 with a saturated solution of sodium carbonate and steam distilled. The distillate was cooled and the white solid filtered therefrom and air-dried overnight. The aqueous filtrate was extracted three times with 100 ml . portions of ethyl ether. The combined ether extracts were dried, filtered, and evaporated to yield additional product which was combined with the previously recovered product. The product had a melting point of about 73-75°C. and weighed 35 g. (88 percent of theory). It was identified by n.m.r. spectra and elemental analyses as 5-bromopyrimidine.
Other solvents were used in the reaction as set forth in the following table.
Example Compound Solvent Temp. 2 Pyrimidine *HC1 benzonitrile 125-128eC. 3 Pyrimidine *HC1 o-nitrotoluene 130eC. 4 Pyrimidine *HC1 o-dichlorobenzene 130°C. 5 Pyrimidine *HC1 o-nitroanisole 130°C.
Example 6 3-Bromoquinoline Λ slurry of 33.3 g. (0.20 mole) of quinoline hydrochloride in 50 ml. of nitrobenzene, contained in a 250 ml. three-neck round-bottom flask equipped with a paddle stirrer, condenser, dropping funnel, and thermometer, was heated to 177-180°C., and 35.2 g. (0.22 mole) of bromine was added drop wise via the dropping funnel over a period of 1 and 1/2 hours The temperature was maintained at about 180°C, and the mixture stirred for an additional 3 hours and 20 minutes, at which time the evolution of hydrogen chloride had ceased.
Heating was stopped, the reaction product mixture was cooled to room temperature, and 200 ml. of benzene was added. The mixture was filtered, and the solid on the filter was washed with 100 ml. of benzene, and sucked dry on the filter. In this manner, 48.7 g. of crude product was obtained. This crude product was added to 200 ml. of water and the mixture made basic with saturated aqueous sodium carbonate solution. The basic mixture was extracted four times with 200 ml. portions of ether. The combined ether extracts were dried, and the solvent was removed in vacuo, leaving 35.1 g. of a pale yellow oil which solidified on standing in the refrigerator. The solid had a melting point of about 12-13°C, and was identified as 3-bromoquinoline. Yield, 84.5 percent of theory; VPC purity, 97 percent.
Example 7 4-Bromoisoquinoline The same general procedure set forth in Example 1 above was followed. In a flask equipped with a reflux condenser, dropping funnel, thermometer, and stirrer was placed 1 33.3 g. (0.20 mole) of isoquinoline hydrochloride, together with 50 ml. of nitrobenzene, and the mixture was stirred and heated to about 180°C. to give a clear yellow solution. To this solution was added dropwise, via the dropping funnel, over a period of 1 hour and 13 minutes, 35.2 g. (0.22 mole) of bromine. The evolution of hydrogen chloride was smooth from the start to the completion of the addition of the bromine. After all the bromine had been added, the reaction mixture was of a single phase, amber red in color. Heating at about 180°C. and stirring were continued after addition of the bromine had been completed. An hour later, a few crystals of a solid material started to collect in the flask near the condenser. After 3 hours and 15 minutes of heating and stirring a very thin slurry of crystals had begun to form and hydrogen chloride evolution had become very slow. After 4 hours and 45 minutes of heating and stirring, the evolution of hydrogen chloride had practically ceased.
The heat source was shut off and the almost clear amber solution was allowed to cool slowly. At about 150°C, crystallization became very rapid. At about 90 °C, 200 ml. of benzene was added to the slurry, and the mixture was stirred for about 15 minutes. The mixture was then cooled to about 20°C. and filtered to yield fine cottony needles which were washed with 100 ml. of benzene, then reslurried with 200 ml. of benzene, filtered off, and dried. The product, which weighed 46.6 g., was placed in 200 ml. of water and the mixture made basic by the addition of a saturated solution of sodium bicarbonate. The basic mixture was extracted four times with 200 ml. portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the ether was evaporated, to yield 33.6 g. of a pale yellow oil, which crystallized on standing. Using vapor-phase chromatography, this crude material was shown to contain 93.5 percent of 4-bromoisoquinoline. The overall yield of 4-bromoisoquinoline was about 80.5 percent. A sample of the crude material was recrystallized from petroleum ether to yield product having a melting point of about 41-42°C.
Example 8 5-Bromo-4-phenylpyrimidine Following the same general procedure set forth above, a mixture of 11.0 g. (0.0572 mole) of 4-phenylpyrimidine hydrochloride in 30 ml. of nitrobenzene, contained in a three-neck flask equipped with stirrer, thermometer, condenser, and dropping funnel, was stirred and heated in an oil bath at about 150°C, and 9.2 g. (0.0575 mole) of bromine was added over a period of 35 minutes. Evolution of hydrogen chloride began immediately. The reaction mixture was heated and stirred about 5.5 hours at 150°C. after addition of the bromine .
At the end of that time the reaction product mixture was cooled to about 105°C. and 100 ml. of benzene was added. Cooling was continued and at about 47 °C. a brown solid separated and a slurry formed. The mixture was stirred for about 20 minutes while cooling to room temperature. The solid material which separated was filtered off, and the filtrate, a mixture of nitrobenzene and benzene, was saved for further work-up. The gummy solid on the Buchner funnel was then suspended in water and the mixture made basic by the addition of 4.2 g. of 50 percent aqueous sodium hydroxide. The basic aqueous mixture was extracted with chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, and evaporated, to give 6.1 g. of a gummy solid.
By vapor-phase chromatography assay, the gummy solid was shown to consist of 71 percent of 4-phenylpyrimidine and 29 percent of the desired product, 4-phenyl-5-bromopyrimidine. An additional 5.9 g. of solid was recovered from the filtrate, referred to above, the combined benzene and nitrobenzene from the beginning work-up of the reaction product mixture. This additional solid material was assayed by vapor-phase chromatography and was determined to contain 39 percent starting 4-phenylpyrimidine and 61 percent 5-bromo-4-phenylpyrimidine . Example 9 3 , 8-Dibromo-l , 6-naphthyridine Following the same general procedure set forth in Example 1, a mixture of 9.8 g. (0.0589 mole) of 1, 6-naphthyridine hydrochloride and 20 ml. of nitrobenzene was heated to 180°C. and bromine (10.36 g., 10 percent molar excess) was added dropwise over a period of about 50 minutes . When the addition of the bromine was complete, the reaction mixture was heated and stirred at about 178-180 °C. for an additional three and one-half hours. The reaction product mixture was then cooled to about 90°C. and 100 ml. of benzene added thereto. A tan solid separated which was filtered off and washed with ether and benzene. The solid weighed about 15 g. This tan solid was added to about 100 ml. of water. The pH of the mixture was adjusted to about 8, using solid sodium carbonate, and the basic mixture extracted four times with 200 ml. portions of chloroform. The combined chloroform extracts were dried and were evaporated to dryness to yield 8.7 g. of a tan solid. Vapor-phase chromatography showed two major components, one of which was the free base of the starting 1,6-naphthyridine and the other appeared to be desired product. The crude product was chromatographed on grade 3 alumina using 5 percent ethyl acetate in carbon tetrachloride as solvent. By this procedure, there was obtained 4.4 g. of product which was identified by n.m.r. spectra as 3, 8-dibromo-l,6-naphthyridine. This material was recrystal-lized from commercial absolute ethanol to yield 3.8 g. of needle-like crystals having a melting point of about 186-188°C.
The bromo-substituted nitrogen-containing hetero-cycles, prepared as set forth above, are useful intermediates in the preparation of compounds having interesting pharmaceutical, veterinary, and agricultural chemical utilities. Thus, for example, the 5-bromopyrimidine is used jin the synthesis of certain substituted 5-pyrimidinemethanols, which are useful either as fungicides for the control of numerous plant pathogenic fungi, or as plant growth regulators. As taught in Belgian Patent 714,003, referred to supra , the synthesis of the 5-substituted pyrimidinemethanols is accomplished by reaction of a ketone with 5-bromopyrimidine in the presence of n-butyllithium at the low temperature of a Dry Ice-acetone cooling bath.
The 4-bromoisoguinoline can be used in the preparation of 4-sulfanilamidoisoquinoline, useful for its antistrep-tococcal properties, as reported by Craig and Cass, J. Am.
Chem. Soc. 64, 783 (1942).
The 3-bromoquinoline can be used in the preparation of a- (2-piperidyl) -3-quinolinemethanol , as reported by Seibert et al. , J. Am. Chem. Soc. 68, 2721 at 2722 (1946). The gulnollnemethanol is reported to possess activity against Lophurae malaria in ducks. See Wiselogle, A_ Survey of Antimalarial Drugs, 1941-1945, Volume 1, page 149, Table 17, (Published by J. W. Edwards, Ann Arbor, Michigan, 1946) .
The 5-bromo-4-phenylpyrimidine has fungicidal activity against Trichophyton mentagrophytes and against Botrytis cinerea .

Claims (12)

What we claim is:
1. A process for brominating a nitrogen-containing heterocyclic compound selected from the group consisting of pyrimidine, quinoline, isoquinoline, 4-phenylpyrimidine, and 1,6-naphthyridine which comprises commingling the nitrogen-containing heterocyclic compound in the form of its hydrogen halide addition salt with a solvent substantially inert to the action of bromine under the conditions of the bromination process, heating and maintaining the mixture at a temperature in the range of from about 125°C. to about 200°C, adding bromine to the heated mixture over a period of time of from about 30 minutes to about 90 minutes, and maintaining the reaction mixture at a temperature of from about 125°C. to about 200°C. for an additional period of time of from about two to about six hours.
2. The process of Claim 1 wherein the solvent is selected from the group consisting of nitrobenzene, o-dichlorobenzene, o-nitroanisole, o-nitrotoluene, and benzonitrile.
3. The process of Claims 1 or 2 wherein the solvent is nitrobenzene.
4. The process of Claims 1 or 2 wherein the solvent is o-dichlorobenzene.
5. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocyclic compound is pyrimidine.
6. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocyclic compound is quinoline.
7. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocyclic compound is isoquinoline.
8. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocycle hydrogen halide is pyrimidine hydrochloride, pyrimidine hydrobromide , pyrimidine hydriodide, quinoline hydrochloride, guinoline hydrobromide, guinoline hydriodide, isoquinoline hydro-bromide, isoguinoline hydrochloride, isoquinoline hydriodide, 4-phenylpyrimidine hydrobromide, 4-phenylpyrimidine hydrochloride, 4-phenylpyrimidine hydriodide, 1,6-naphthyri-dine hydrobromide, 1,6-naphthyridine hydrochloride or 1,6-naphthyridine hydriodide.
9. The process of any of Claims 1 to 5 or 8 wherein the nitrogen-containing heterocycle hydrogen halide is pyrimidine hydrochloride.
10. The process of any of Claims 1 to 4, 6 or 8 wherein the nitrogen-containing heterocycle hydrogen halide is quinoline hydrochloride.
11. The compounds 5-bromopyrimidine, 3-bromoquinoline , 4-bromoisoquinoline, 5-bromo-4-phenyl-pyrimidine, 3,8-dibromo-l,6-naphthyridine whenever prepared by the process of any of Claims 1 to 10.
12. The process of brominating a nitrogen-containing heterocyclic compound as defined in Claim 1, substantially as hereinbefore described with particular reference to the Examples. S. HOROWITZ & CO. AGENTS FOR APPLICANTS
IL43505A 1972-11-21 1973-10-29 Process for bromination of nitrogen-containing heterocyclic compounds IL43505A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US30838972A 1972-11-21 1972-11-21

Publications (2)

Publication Number Publication Date
IL43505A0 IL43505A0 (en) 1974-01-14
IL43505A true IL43505A (en) 1977-04-29

Family

ID=23193800

Family Applications (1)

Application Number Title Priority Date Filing Date
IL43505A IL43505A (en) 1972-11-21 1973-10-29 Process for bromination of nitrogen-containing heterocyclic compounds

Country Status (9)

Country Link
JP (1) JPS596854B2 (en)
BE (1) BE807525A (en)
CH (1) CH584205A5 (en)
DE (1) DE2356358C2 (en)
FR (1) FR2207100B1 (en)
GB (1) GB1439682A (en)
IL (1) IL43505A (en)
IT (1) IT1001824B (en)
NL (1) NL184058C (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2221808C2 (en) * 1972-05-04 1985-06-20 Sandoz-Patent-GmbH, 7850 Lörrach Hydrazinopyridazine derivatives, their acid addition salts, processes for their preparation and medicines

Also Published As

Publication number Publication date
GB1439682A (en) 1976-06-16
NL184058B (en) 1988-11-01
FR2207100A1 (en) 1974-06-14
IT1001824B (en) 1976-04-30
DE2356358A1 (en) 1974-05-30
BE807525A (en) 1974-05-20
IL43505A0 (en) 1974-01-14
NL184058C (en) 1989-04-03
JPS596854B2 (en) 1984-02-15
FR2207100B1 (en) 1981-06-19
DE2356358C2 (en) 1984-12-06
NL7315788A (en) 1974-05-24
JPS4981375A (en) 1974-08-06
CH584205A5 (en) 1977-01-31

Similar Documents

Publication Publication Date Title
US4987232A (en) Preparation of 2-chloropyridine 3-carboxylic acid esters
EP0000106B1 (en) 2-alkyl nicotinoids and processes for their production and use
JPH0778065B2 (en) (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O ▲ above 3 ▼, O ▲ above 4) bis (acyloxy-O) Boron compound, salt thereof, and method for producing the same
US4066665A (en) 2-Alkylamino-α-phenyl-1-cyclohexene-1-methyleneimine, its salts and preparation
US3956301A (en) Process for bromination of pyrimidine
EP0052333B1 (en) 4-fluoro-5-oxypyrazole derivate and preparation thereof
NO166712B (en) PROCEDURE FOR THE PREPARATION OF PYRROLIDO DERIVATIVES.
IL43505A (en) Process for bromination of nitrogen-containing heterocyclic compounds
JPS6117826B2 (en)
US4167638A (en) Process for production of 8-NHR quinolines
US4894457A (en) 7-bromo-beta-carboline compound and method for producing same
US4864032A (en) Process for the preparation of indazoles
JP4231556B2 (en) Process for producing 1,3-disubstituted 2-nitroguanidine
US3725422A (en) New organic sulfur compounds and methods for their production
WO1989006230A1 (en) Cyano-dienes, halopyridines, intermediates and a process for their preparation
US3433802A (en) 3-(n-lower-alkylanilino)pyrrolidines
US4062891A (en) N-formyl-2,3,5,6-dibenzobicyclo[5.1.0]octan-4-methylamine
NO830877L (en) TRICYCLIC DERIVATIVES OF 5,6-DIHYDRO-11H-DIBENZO- (B, E) AZEPIN-6-ON WITH PHARMACOLOGICAL ACTIVITY AND PROCEDURE FOR THEIR PREPARATION
AU2004232454B2 (en) Method for the production of nicotinaldehydes
US2696488A (en) 2, 4, 6-tris-(1-piperidyl)-5-benzylpyrimidine and process of preparing same
EP0013726B1 (en) Indanyloxamic derivatives, their preparation and pharmaceutical compositions containing them
US20040186300A1 (en) Process for the preparation of zafirlukast
Van Heyningen 3-Benzoyl-4-piperidones
KR790001654B1 (en) Process for the preparation of s-triazolo(3,4-b)benzothiazoles
KR790001652B1 (en) Process for the preparation of s-triazolo(3,4-b)benzothiazoles