KR810001201B1 - Method of preparation for the 4-alkyl-2-fluoro biphenyl - Google Patents

Abstract

Title compd. (I; R2 = methyl, ethyl), useful as an intermediate for pharmaceuticals, was prepd. by the fluorination, diazotization of II(R1 = nitro, amino). II was prepd. by the reaction of benzene and III at 25-70oC. Thus, 15 g pentyl nitrite and 8 g 2-nitro-4-methylaniline were reacted in benzene at 40oC to give 5.9 g 2-nitro-4-methylbiphenyl.

Description

Method for preparing 4-alkyl-2-fluoro biphenyl

The present invention relates to a process for the preparation of 4-alkyl-2-fluoro biphenyls of general formula (I).

In formula, R <2> is alkyl groups, such as methyl and an ethyl group.

These are the starting materials for the production of 3-fluoro-2-phenylhydrothromic acid, which is used as an anti-inflammatory analgesic.

The materials of the present invention have the structure of formula (II)

In formula, R <1> is a nitro group, an amino group, or fluorine, and R <2> represents alkyl groups, such as a methyl group and an ethyl group.

Materials having the general formula (Ⅱ) R ¹ is a nitro group or an amino group of the R ¹ are the starting materials for the preparation of a fluorine material that is 4-alkyl-2-fluorobiphenyl.

In other words, the amino acid is replaced with fluorine in a modified Schmanmann reaction. Starting materials for biphenyl synthesis are aminoalkylbenzenes such as P-toluidine and P-aminoetherbenzene, so that the alkyl group at the carbon 4-position of biphenyl, that is, R ² , can be variously changed.

The materials of the present invention can be prepared in a variety of ways that will become brittle.

The present invention is characterized in that the yield is high by setting a new optimal reaction method and conditions for the synthesis of the materials in the invention, and the reaction processes are simpler than the processes of known reactions, so that there is little industrial difficulty.

The main synthetics of the present invention and the characteristics of the method of synthesizing them are as follows.

[Biphenylation Reaction and Biphenyl Derivative]

There are many methods for producing biphenyl, but industrially useful reaction processes are reduced to the following two.

For example, there is a Gombelk-Bachmann method for diazotizing an amine with nitrite and an acid and reacting it with benzene to produce biphenyl, and the Uulmann method for heating halobenzenes with copper powder.

The Gombelk-Bachmann method is difficult to industrialize by setting consistent reaction conditions due to the difficult reaction conditions and manipulation before and after the reaction.

The Uulman method requires the reaction of halobenzenes with different structures in synthesizing asymmetric biphenyls, resulting in a large number of isomers, which lowers the yield of the target substance and causes separation.

In the present invention, by using an alkyl nitrite as a diazotizing agent, the biphenyl reaction can be performed in one step reaction in a benzene solution which is a solvent and a reactant.

Therefore, the present invention is characterized in that the process is simple and the yield is easily increased. For example, alkylnitrite earth uses nitrites of alkoxy alcohols of C ₄ -C ₆ , and the choice of suitable alkylnitrites is stable at a given reaction temperature, and the decomposition rate of nitrozo groups must be constant. By-products, alcohols derived from nitrite should be readily separable when treating the product. The yield of biphenylation depends on the reaction temperature, the order of addition of starting materials, the rate of addition and the reaction time, and the kind of alkylnitrite mentioned above also plays a big role in improving the yield.

The reaction temperature is in the range of 25-70 ° C, the temperature at which nitrogen begins to be generated. The reaction time is 5-48 hours depending on the type of alkylnitrite.

The starting material of the biphenyl-containing excess of benzene (25-250 times) is used to prevent side reactions other than the reaction of the aniline derivatives of general formula (III) with benzene.

However, if the dilution degree of benzene increases, the reaction with aniline can be prevented, but the reaction time is slowed down, so the reaction time is required for a long time. The rate of addition of alkylnitrite to aniline and benzene solutions also has a significant effect on yield.

[Reduction of Nitro Group in General Formula (II)]

4-alkyl-2nittophenyl is converted to 4-alkyl-2-aminobiphenyl almost quantitatively by metal catalyst reduction, i.e. using a palladium catalyst. This catalyst does not reduce its activity even when used over three orders.

The general method of reducing to iron, zinc, tin, or salts and acids is not only complicated after treatment but also poor in yield.

[Fluorine Substitution of Amino Group in General Formula (II)]

Aromatic amino groups can be substituted with fluorine by Schmanne reaction, but the amino groups of 4-alkyl-2-aminobiphenyl obtained above are not fluorinated in satisfactory yields. However, the fluorination method of the present invention has succeeded in obtaining a fluorine substituent with good yield by adopting a new reaction method and optimum reaction conditions.

That is, diazotization in the presence of tetrahydrofuran increases the solubility of aniline, so that the diazo reaction occurs in solution, and the reaction occurs easily quantitatively.

On the other hand, the addition of tetrahydrofuran reduces the solubility of diazotetrafluoroborate and increases the stability of the salt.

Thus diazotetrafluorobutyrate can be obtained in quantitative yield.

4-alkyl-2-fluorobiphenyl synthesis, the final product of the present invention, is a mixed solution of tetrahydrofuran and benzene which avoids high temperature decomposition of known diazotetrafluoroborate and helps stabilize tetrafluoroborate. Liquid phase decomposition results in improved yields. The following examples illustrate the present invention in more detail, but the content of the present invention is not limited only to the examples.

Example 1

15 g of pentylnitrite and 150 cc of benzene are added to a three neck flask and the temperature is 40 ° C. 8 g of 2-nitro-4-methylaniline are dissolved in 100 cc of benzene and the solution is added dropwise to 40 ° C. pentylnitrite and benzene solution over 2 hours. After dropping, reflux until no generation of nitrogen is noticed. Benzene was recovered by distillation and 150cc of petroleum ether was added to the remaining oil, followed by extraction with stirring.

The petroleum ether was washed with 100cc of 5% hydrochloric acid, distilled and recovered. The remaining oil was distilled under 2 mmHg pressure reduction to collect 180-200 ° C of distilled fraction, which was recrystallized with ethyl alcohol to obtain 5.9 g of 2-nitro-4-methyl ratio. Phenyl was obtained. Yield 52% Welding 49 ℃

Example 2

8.4 g of 2-nitro-4-methyl biphenyl was dissolved in 50 cc of ethyl alcohol and added to a hydrogenation vessel. 100 mmg of 10% palladium-activated carbon was added thereto, followed by reaction under hydrogen pressure of 50 psi.

When there is no change in pressure, the reaction solution is filtered and the alcohol is distilled off. The remaining oil was distilled at 140-150 ° C. under 1-2 mm Hg vacuum to obtain 7.0 g of 2-amino-4-methylbiphenyl. Yield 96%

Example 3

1.8 g of 2-amino-4-methyl biphenyl is dissolved in a mixture of 3 cc hydrochloric acid, 2 cc tetrahydrofuran and 10 cc water. After the solution is brought to -5 °, 0.69 g of sodium nitrite is dissolved in 2 cc of water and added at a time while stirring. Add 5 cc of 48% tetrafluoroboric acid at once and stir for 30 minutes at 10 ° C or less. The resulting solid is filtered, washed sequentially with cold water, cold ethyl alcohol and dried in air. 2-diazo-4methylbiphenyltetrafluoroborate was obtained. Yield: 91%

Decompose at melting point 78-80 ° C.

Example 4

10 cc of benzene and 2 cc of tetrahydrofuran are added to the flask and the cooler is attached and heated until boiling.

To this was added 2.8 g of 2-diazo-4-methylbiphenyltetrafluoroborate in small amounts. It is further refluxed for 30 minutes after generation of nitrogen is stopped. The reaction is washed with water until neutral and dried over drying calcium chloride. Benzene and tetrahydrofuran were distilled off, and the remaining oil was distilled off under reduced pressure of 2 mmHg to obtain 1.4 g of 2-fluoro-4-methyl biphenyl at 100-120 ° C. in 75% yield.

Example 5

15 g of pentylnitrite are mixed with 200 cc of benzene and the solution is heated to 40 ° C. A solution of 8.4 g of 2-nitro-4-ethyl aniline dissolved in 200 cc of benzene was added dropwise over 2 hours and refluxed for 90 minutes. The benzene was distilled off and 150cc of petroleum ether was added to the remaining oil, followed by extraction with stirring.

The petroleum ether solution is washed with 100 cc of 5% hydrochloric acid and then dried over calcium chloride. The petroleum ether was distilled off, and the remaining oil was distilled off under reduced pressure of 2 mmHg to collect a distillate of 180-190 ° C., which was recrystallized with ethyl alcohol to obtain 5.6 g of 2-nitro-4-ethyl biphenyl.

Yield 46% Melting Point 45 ℃

Example 6

In a hydrogenation vessel, 8.4 g of 2-nitro-4-ethylbiphenyl is dissolved in 50 cc of ethyl alcohol, 100 mg of 10% palladium-activated carbon is added, and reacted at 50 psi of H ₂ until there is no pressure change. The catalyst was removed, ethyl alcohol was distilled off, and the remaining oil was distilled at 120-130 ° C. under 2 mmHg pressure to obtain 7.0 g of 2-amino-4-ethyl biphenyl. Yield: 92%

Example 7

4.0 g of 2-amino-4-ethyl biphenyl are dissolved in 5 cc of hydrochloric acid, 4 cc of tetrahydrofuran and 20 cc of water, and the reaction temperature is brought to -5 ° C while stirring. 1.4 g of sodium nitrite is dissolved in 5 cc of water and added at once.

Add 10 cc of 48% tetrafluoroboric acid at once and stir at 10 ° C or less for 30 minutes. The product is collected by filtration, washed with cold water and cold ethyl alcohol in turn and dried in air.

4.95 g of 2-diazo-4-ethyl biphenyl tetrafluoroborate were obtained. Yield: 84% Decomposition at 50-52 ° C.

Example 8

Mix 20 cc of benzene and 4 cc of tetrahydrofuran in the flask and heat it to 50 ° C. 5.2 g of 2-diazo-4-ethylbiphenyl tetrafluoroborate are added in small portions to avoid reaction. It is further refluxed for 30 minutes after generation of nitrogen is stopped. The reaction was washed with water until neutral, dried over calcium chloride, distilled and recovered benzene and tetrahydrofuran, and the remaining oil was distilled at 90-100 ° C. under 2 mmHg reduced pressure to yield 2-fluoro-4-ethyl ratio. 2.5 g of phenyl were obtained. Yield: 70%

Claims (1)

An aniline derivative of formula (III) and benzene were reacted at 25-70 ° using an alkylnitrite of C ₄ -C ₆ aliphatic alcohol as a diazotizing agent to synthesize a biphenyl derivative of formula (II), This nitro group is reduced to an amino group using a palladium catalyst, and this amino compound is diazotized in a tetrahydrofuran solution and then reacted with tetrafluoroboric acid to obtain tetrafluorotoborate of a diazohydrate, which is tetrahydrofuran. Method for producing 4-alkyl-2-fluorobiphenyl of the general formula (I), characterized by fluorination by heating to 30-100 ° C. in a mixed solution of benzene.

However, R1: nitro group, amino group R2: Alkyl groups, such as methyl and ethyl