JPS596854B2 - Bromination method for heterocycle-containing heterocyclic compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for β=bromination of nitrogen-containing heterocyclic compounds.

According to the present invention, a nitrogen-containing heterocyclic compound is subjected to bromination at elevated temperature in the form of its hydrologonic acid addition salt in a solvent substantially inert to the action of bromine under the conditions of the bromination reaction. The above nitrogen-containing heterocyclic compound can be subjected to β-bromination (bromination of the carbon atom at the β-position of the nitrogen atom of the heterocyclic compound) by reacting with . The products according to the invention, such as 5-brompyrimidine, have proven useful as intermediates in the synthesis of several new agricultural drugs, particularly interesting plant growth regulators and plant fungicides. Since these drugs are important substances,
The present inventor has begun research on a simpler method for synthesizing 5-brompyrimidine, which is an important intermediate thereof. Previously, Bredereck et al. taught the following method [Hemitsier Berichte Vol. 91, 384]
2832 (1958) on page 8].

That is, a mixture of pyrimidine hydrochloride and bromine is heated to about 160°C on an oil bath for about 3 hours to form a solid reaction product, and the temperature of the oil bath is further increased to 250°C to produce 5-bromine. The pyrimidine hydrobromide salt is sublimed from the solid reaction mixture under reduced pressure. The 5-bromopyrimidine hydrobromide is taken up in sodium sulfite solution, made alkaline with potassium hydroxide and extracted with chloroform.
A method for producing pure 5-bromopyrimidine by distilling off chloroform is presented. Other methods for the synthesis of 5-bromopyrimidine have also been reported by Bredereck et al.
803 (1962)].

That is, 2-bromo-1,1,3,3-tetraethoxypropane can be obtained by brominating 1,1,3,3-tetraethoxypropane in carbon tetrachloride. In addition, 2-bromo 1.
It has been reported that 5-bromopyrimidine can be obtained by condensing 1,3,3-tetraethoxypropane and formamide. A method for producing 4-bromoisoquinoline has been reported by Gilman et al.
The Journal of the American Chemical Society, Vol. 69, p. 1946 (1947)].

Prolonged heating of isoquinoline perpromide hydrobromide produces a solid. Excess sodium hydroxide aqueous solution is added to this, and the liberated 4-bromoisoquinoline is recovered by steam distillation. This crude product is purified by recrystallization from petroleum ether. A method for producing 5-bromo-4-phenylpyrimidine in a six-step synthetic process has been reported by VanderPlas 84, p. 1101 (1965)].

He states that the direct bromination method of Bredereck et al. is not suitable for the synthesis of 5-bromo-4-phenylpyrimidine because the phenyl group is easily attacked by the bromination agent.
Quinolymph furomide/hydrobromide 180-200
A production method for obtaining 3-promquinoline by thermal decomposition at °C has been reported by Ishiyu [The Journal of Organic Chemistry Vol. 1, Vol. 27, p. 1318 (1).
962)].

The present invention relates to β-bromination of nitrogen-containing heterocyclic compounds, and in particular, pyrimidine, 4-bromination,
phenylpyrimidine, quinoline, isoquinoline and 1
- A nitrogen-containing heterocyclic compound selected from 6-naphthyridine can be β-brominated. The process of the present invention involves adding a heated mixture of a solvent substantially inert to the action of bromine under the reaction conditions and a hydrologenide salt of a nitrogen-containing heterocyclic compound at a constant rate over a period of time. It consists of adding bromine. The present invention provides a method for obtaining a β-bromo-substituted nitrogen-containing heterocyclic compound, such as 5-bromopyrimidine, in good yield, and is a commercially applicable method.

It has been found that this method is generally applicable to nitrogen-containing heterocyclic compounds. The production of the β-bromo-substituted nitrogen-containing heterocyclic compound is advantageously carried out using a hydrohalic acid addition salt of the nitrogen-containing heterocyclic compound.

Suitable hydrohalic acid addition salts include hydrochloride, hydrobromide, hydroiomonide, such as pyrimidine hydrochloride,
Pyrimidine hydrobromide, pyrimidine hydroiomonide, quinoline hydrochloride, quinoline hydrobromide, quinoline hydroiomonide, isoquinoline hydrobromide, isoquinoline hydrochloride , isoquinoline hydroiomonide,
4-phenylpyrimidine hydrobromide, 4-phenylpyrimidine hydrochloride, 4-phenylpyrimidine hydroiomonide, 1,6 naphthyridine hydrobromide, 1,6
-Includes naphthyridine hydrochloride and 1,6-naphthyridine hydroiomonide. Of these hydrohalides, the hydrochloride salt is preferred for use in the bromination of this invention.
The nitrogen-containing heterocyclic compound/hydrohalide is suspended or dissolved in a suitable reaction solvent, heated, and bromine is added thereto.

Bromine and the nitrogen-containing heterocyclic compound/hydrohalide first form a complex, and this complex is dissolved in the reaction solvent. The solvent is chosen to be substantially inert towards bromine under the conditions of this reaction. A preferred solvent does not dissolve the starting material, the nitrogen-containing heterocyclic compound/hydrohalide, but completely dissolves the complex of bromine and the nitrogen-containing heterocyclic compound/hydrohalide, and A bromine-substituted nitrogen-containing heterocyclic compound, which is a substance, is a solvent that does not substantially dissolve the hydrologenide salt. Such preferred solvents include inorganic solvents such as thionyl chloride and phosphorus oxychloride, and carbon tetrachloride, nitrobenzene, orthodichlorobenzene, chlorobenzene, orthonitrotoluene,
Examples include organic solvents such as benzonitrile, orthonitroanisole, orthochloroanisole. All these solvents are substantially inert towards bromine under the conditions of the new process of the invention. All of the above-mentioned solvents are useful for obtaining the target substance, a bromine-substituted nitrogen-containing heterocyclic compound, in a good yield, but organic solvents are especially useful for ease of handling and possibility of reuse. More desirable. The organic solvents benzonitrile, o-nitrotoluene, o-dichlorobenzene, o-nitroanisole and nitrobenzene are particularly useful since they can be obtained in good yields. Among these organic solvents, o-dichlorobenzene and nitrobenzene are preferred, and nitrobenzene is particularly preferred. Solvents are an important part of this invention.

The solvent helps regulate the temperature of the reaction mixture and allows better mixing of the bromine and the nitrogen-containing heterocyclic compound/hydrohalide. The solvent allows stirring of the reaction mixture throughout the reaction. It also makes it possible to obtain a higher yield of product than without the solvent. In contrast to the prior art, where the reaction product mixture becomes solid as the reaction progresses, the reaction product mixture of the process of the invention can be stirred. The presence of a solvent further facilitates the separation of the β-bromo substituted nitrogen-containing heterocyclic compound. In the presence of an inert solvent, the reaction mixture exists in the reaction vessel as a slurry rather than a solid upon completion of the reaction, and the crude target product can be removed from the solvent. This is advantageous, especially in the case of mass production, compared to separating the product from the reaction vessel by sublimation or scraping. The presence of an inert solvent thus greatly aids in carrying out mass production. The bromination reaction is carried out, for example, by suspending the hydrohalic acid addition salt of the nitrogen-containing heterocyclic compound in an inert solvent such as nitrobenzene, and heating the mixture to an appropriate temperature.

Suitable temperatures vary depending on the heterocyclic reactant and range from about 125°C (for pyrimidines) to about 200°C (for quinolines). The bromine is added to the heated mixture over a period of about 30 to about 90 minutes.

This addition is preferably carried out at a rate such that the reaction between the bromine and the nitrogen-containing heterocyclic compound is well controlled. In the laboratory, it is preferred to add the bromine dropwise over a period of 30 to 90 minutes. Although the reaction may be completed even if bromine is added unevenly at unequal intervals, it is preferable to complete the reaction by adding equal amounts at equal time intervals. Upon addition of bromine... hydrogen halogenide is evolved from the reaction mixture.

The rate of hydrogen halide generation is regulated by the rate of bromine addition. Controlling the generation rate of hydrogen halide is important. If hydrogen halide is generated too rapidly, there is a risk that the added bromine will be accompanied. This entrainment results in loss of bromine, lowering product yield and increasing production costs. Control of the hydrogen halide generation rate is also important in that it is desirable to pass the gas resulting from the reaction through a gas scrubber to remove the hydrogen halide. Such removal is desirable as a measure to avoid polluting the atmosphere as much as possible. Thus, whether the reaction is carried out on a laboratory scale or on a commercial scale, the addition of bromine prevents entrainment and loss of bromine to the hydrogen halide and ensures that sufficient hydrogen halide is removed from the gas produced by the reaction. It is desirable to carry out the process at a rate that allows the rate of generation of hydrogen halide to be controlled so that it can be removed. After the bromine addition is complete, the reaction mixture is heated for an additional period of time, about 2 to 6 hours, to complete the reaction. As a result, the complex of the intermediate hydrohalide of the nitrogen-containing heterocyclic compound and bromine is thermally decomposed, and the desired hydrohalide of the β-brome compound is formed. Heating for too long will reduce the yield of the target product and should be avoided. The heating time also depends on the heterocyclic compound to be brominated. At the end of heating, the reaction product mixture is fed to the final step in a conventional manner.

That is, the reaction product mixture is cooled to some extent and a solvent, such as benzene, is added. Other solvents that can be used include hexane, ether, toluene, and xylene. The added solvent dilutes the inert solvent and serves to separate the target substance from the inert solvent. After adding the diluent solvent, the mixture is further cooled to about room temperature. The solids precipitated on cooling are collected by filtration. This solid is a hydrologenide salt of a β-bromine-substituted nitrogen-containing heterocyclic compound. The free base of the β-brome substituted nitrogen-containing heterocyclic compound is obtained by suspending this salt in water, adjusting the pH to about 8 to 10 with a strong base, and steam distilling it. Suitable strong bases include sodium hydroxide, potassium hydroxide and sodium carbonate. The product is extracted from the cooled distillate. Alternatively, the product can also be obtained by extraction with chloroform or ether from the basic mixture. By drying the chloroform or ether extract and distilling off the solvent under reduced pressure, a β-brome substituted nitrogen-containing heterocyclic compound can be obtained. Next, specific embodiments of the present invention will be described with reference to Examples.

The technical scope of the present invention is not limited to the scope described in the Examples. Example 1 Preparation of 5-bromopyrimidine: 30 ml of nitrobenzene and 29.0 y of pyrimidine hydrochloride (0.0 ml) and 29.0 y of pyrimidine hydrochloride were placed in a 250 me three-neck round bottom flask equipped with a spatula stirrer, condenser, addition funnel and thermometer. A slurry of 25 mol) of bromine was heated to about 130°C, and
y (0.275 mol) is added dropwise through the addition funnel over a period of 30 minutes.

The mixture is further heated and stirred at about 130°C for 2 hours. After the reaction is complete, the reaction mixture is cooled to about 80° C. and 150 ml of benzene are added. Filter the resulting slurry. The solid collected by filtration is washed with 100 ml of benzene and sucked dry. 61.07 of the dry tan solid is placed in 200 me of water. The aqueous mixture is adjusted to pH 8 with saturated aqueous sodium carbonate solution and steam distilled. Cool the distillate and filter off the white solid and air dry overnight. Transfer the aqueous filtrate to ethyl ether
Extract 3 times with 00me. The ether extracts are combined, which is dried, filtered and evaporated to give further product, which is combined with the same product as the compound obtained previously. Product melting point approximately 73
~75℃. Yield: 357 (88% yield). It was confirmed to be 5-brompyrimidine by nuclear magnetic resonance spectroscopy and elemental analysis. Examples 2 to 5 Using the solvents listed in the middle column of Table 1, the same procedure as in Example 1 was carried out to obtain 5-bromopyrimidine at the yield shown in the rightmost column of the same table.

Example 6 Preparation of 3-bromoquinoline: 33.3y (0.20 mol) of quinoline hydrochloride in a 250 ml three-sided round bottom flask equipped with a paddle stirrer, condenser, dropping funnel and thermometer. Nitrobenzene 50ml
The slurry of 35% bromine was heated to 177-180°C.
27 (0.22 mol) was added dropwise through the dropping funnel over a period of 1.5 hours.

The temperature was maintained at about 180° C. and the mixture was stirred for an additional 3 hours and 20 minutes until hydrogen chloride evolution ceased. Stop heating, cool the reaction mixture to room temperature, and add 200 me of benzene.
The mixture is filtered and the solid is filtered off, washed with 100w11 of benzene and sucked dry on the filter. 48.7y of crude product are thus obtained. 200 ml of water are added to the crude product, which is made basic by adding saturated aqueous sodium carbonate solution. The basic mixture is extracted four times with 200 ml of ether. The ether extracts are combined, dried and the solvent removed under reduced pressure to give a pale yellow oil, 35.1y. Place this oil in the refrigerator to solidify. The melting point of this solid is approximately 1
The temperature was 2 to 13°C, and it was confirmed that it was 3-bromoquinoline. Yield 84.5%, purity 97% by gas phase chromatography Example 7 Production of 4-bromiisoquinoline: The following procedure was carried out in the same manner as in Example 1 above.

In a flask equipped with a reflux condenser, dropping funnel, thermometer and stirrer, add isoquinoline hydrochloride 33,3f7 (0.
20 mol) with 50 ml of nitrobenzene and the mixture is stirred and heated to about 180° C. to obtain a clear yellow solution. Bromine 35.2y (0.22 mol) is added dropwise to this solution through an addition funnel over a period of 1 hour and 13 minutes.
Hydrogen chloride evolution was smooth throughout the bromine addition. After all the bromine has been added, the reaction mixture is a single layer and amber red in color. After adding the bromine, it is further heated to about 180° C. and stirring is continued. After 1 hour solid crystals begin to precipitate in the flask near the condenser.

After heating and stirring for 3 hours and 15 minutes, a very dilute slurry of crystals begins to form and hydrogen chloride evolution becomes very slow.

When heating and stirring were continued for 4 hours and 45 minutes, the generation of hydrogen chloride virtually stopped.

Remove the heat source and allow the almost clear amber solution to cool slowly.

It crystallizes rapidly at about 150°C. Benzene 2 at about 90℃
Add 00me to this slurry and stir the mixture for about 15 minutes. The mixture is then cooled to about 20° C. and filtered to obtain fine cotton-like needles. This is washed with 100 ml of benzene, then reslurried with 200 ml of benzene, filtered, and dried. The product obtained 46
．． 6V in 200 ml of water and made basic by adding saturated sodium bicarbonate solution. This basic mixture is extracted four times with 200 ml of ether. Combine the ether extracts,
Dry with anhydrous magnesium sulfate. Filter the desiccant and evaporate the ether layer to obtain a pale yellow oil, 33.6f7. If left alone, it will crystallize. Vapor phase chromatography showed that the crude material contained 93.5% 4-bromoisoquinoline. The overall yield of 4-bromoisoquinoline was about 80.5%.

The crude material was recrystallized from petroleum ether to a melting point of about 41-4
Obtain the product at 2°C. Example 8 Preparation of 5-bromo-4-phenylpyrimidine: According to the method of the above example, 4-phenylpyrimidine.
A mixture of 11.07 (0.0572 mol) of hydrochloride and 30 ml of nitrobenzene was added, stirred, and heated on an oil bath for about 15 minutes.
Heating at C, bromine 9.2y (0.0575 mol) was
It takes 5 minutes to drip.

Hydrogen chloride generation begins immediately. The reaction mixture is heated and stirred at 150° C. for approximately 5.5 hours after addition of the bromine. The reaction mixture was then cooled to about 105°C and diluted with benzene 10
Add 0m'.

Further cooling is continued and at about 47° C. a brown solid separates to form a slurry. Cool the mixture to room temperature while stirring for about 20 minutes. The precipitated solid material is removed and the filtrate, a mixture of nitrobenzene and benzene, is saved for further processing. The gummy material on the Buchna funnel is suspended in water and the mixture is made basic by adding 4.27 g of 50% aqueous sodium hydroxide solution. The basic aqueous mixture is extracted with chloroform. The chloroform extracts are combined, dried over anhydrous magnesium sulfate and evaporated to give a gummy solid 6.1y. Vapor phase chromatography analysis showed that the gummy solid consisted of 71% 4-phenylpyrimidine and 29% of the desired product, 4-phenyl-5-bromopyrimidine. An additional 5.97 ml of solid material was recovered from the filtrate consisting of a mixture of nitrobenzene and benzene from the first treatment of the reaction mixture. This solid was quantified by vapor phase chromatography and confirmed to contain 39% of the raw material 4-phenylpyrimidine and 61% of the product 5-bromo-4-phenylpyrimidine. Example 9 Preparation of 3,8-dibromo-1,6-naphteridine: According to the method described in Example 1, 1,6-naphteridine hydrochloride 9.8f1 (0.0589 mol) and nitrobenzene 2
0 ml of the mixture is heated to 180° C. and bromine 10.367 (10% molar excess) is added dropwise over a period of approximately 50 minutes.

After the prom addition is complete, the reaction mixture is heated and stirred for an additional 3.5 hours at about 178-180°C. The reaction mixture is cooled to about 90° C. and 100 ml of benzene are added thereto. The tan solid formed is filtered off and washed with ether and benzene. Approximately 157 ml of solid is obtained. This tan solid is placed in about 100 ml of water. The pH of the mixture is adjusted to about 8 using solid sodium carbonate and the basic mixture is extracted 4 times with 200 ml of chloroform. The chloroform extracts are combined, dried and the chloroform is evaporated to dryness to yield 8.7y of a tan solid. Vapor phase chromatography shows that it consists of two main components: the free base of 1,6-naphthyridine, which is the starting material, and the target material. This crude product was purified using a 5% ethyl acetate solution in carbon tetrachloride.
Chromatographed on grade 3 alumina. This yielded 4.47 of the target substance. This was confirmed to be 3,8-dibromo-1,6-naphthyridine by nuclear magnetic resonance spectroscopy. This material was recrystallized from commercially available absolute ethanol to a melting point of approximately 186-188°C.
3.8y of needle-like crystals are obtained. The various bromine-substituted nitrogen-containing heterocyclic compounds obtained in the above examples are useful as intermediates for producing interesting pharmaceuticals, veterinary medicines, and agricultural chemicals.

For example, 5-prompimyridine is utilized in the synthesis of certain substituted 5-pyrimidine methanols that are useful as fungicides for the control of many phytopathogenic fungi or as plant growth regulators. In this regard, Pelkey Patent No. 714003, cited in the above-mentioned document, discloses that 5-bromopyrimidine is prepared by reacting a ketone with 5-bromopyrimidine in the presence of n-butyllithium at the low temperature of a dry ice-acetone cold bath. A synthetic method for obtaining substituted pyrimidine methanol is disclosed.
4-bromoisoquinoline can be used to make 4-sulfanylamide isoquinoline.

This material is known by Craig and Ca
ss) [The Journal of the American Chemical Society, Vol. 64, p. 783 (19
42), it is useful as an antibacterial agent. 3-Bromoquinoline is available from Sejbe
α-(2-piperidyl)-3-quinoline as reported by [The Journal of the American Chemical Society Vol. 68, p. 2722, 2721 (1946)]. It can be used in the production of methanol.

This quinoline methanol compound has been reported to have activity against Lophurae malaria in ducks (WiselOgle, A Survey of Antimalarial Drugs, 1941-1945).
Publisher: Jie Doubleu Edwards, Ann Alba, Michigan, USA (published in 1946) Volume 1, page 149 Table 1
7]. 5-bromo-4-phenylpyrimidine is trichophyton. , Mentagrophytes (TrichOpl)
lytOnmentagrOphytes) and Botrytiscinerea
) has antibacterial activity against

Claims (1)

[Claims] 1. Hydrochloride or hydrobromide of a nitride-containing heterocyclic compound selected from the group consisting of pyrimidine, quinoline, isoquinoline, 4-phenylpyrimidine and 1,6-naphthyridine is treated under bromination reaction conditions with the action of bromine. and a solvent that is substantially inert to
5-bromopyrimidine consisting of heating and holding at a temperature of 25°C to 200°C, gradually adding bromine to this heated mixture, and after the addition is complete, holding the reaction mixture at 125°C to 200°C for a further 2 to 6 hours. , 3-bromoquinoline, 4-
An improved method for producing a β-bromo nitrogen-containing heterocyclic compound selected from the group consisting of bromoisoquinoline, 5-bromo-4-phenylpyrimidine and 3,8-dibromo-1,6-naphthyridine, the solvent being nitrobenzene. , benzonitrile, o-nitrotoluene, o-dichlorobenzene, and o-nitroanisole.