NL8006497A - PROCESS FOR PREPARING ARYL-PROPIONIC ACIDS. - Google Patents

Description

! I

,; 1,: r

Process for preparing arylpropionic acids.

The invention relates to a process for preparing 2-arylpropionic acids, which, as is known, have valuable therapeutic properties, for example anti-inflammatory activity.

According to the invention there is provided a process for preparing a compound of the formula 1 wherein n is an integer from 1 to 4 and each fl, whether or not equal to aralkyl, cycloalkyl, alkyl-substituted cycloalkyl, cycloalkenyl, aryl, alkoxy, aralkoxy, cycloalkoxy, aryloxy, alkylthio, aralkylthio, cycloalkylthio, arylthio, aryl (dialkoxy) methyl, aryl (alkylenedioxy) methyl, N-alkyl-N-arylamino, trifluoromethyl, fluoro, chloro, dialkylamino, al or unsubstituted pyridyl, piperidyl, furyl, N-alkylmorpholino, N-alkylthiomorpholino, pyrrolinyl, pyrrolidinyl, pyrrolyl or thienyl, two Qs together form a heterocyclic ring, or Q together with 9H-carbazol-3-yl or substituted naphthyl by 1) reaction of a compound of the formula 3 and ethylene in the presence of a catalyst and 2) carboxylation of the compound of the formula 2 formed therein to a compound of the formula 1.

Examples of the groups indicated for Q include aralkyl, for example benzyl; cycloalkyl with, for example, 3-7 carbon atoms and in particular cyclohexyl; alkyl-substituted cycloalkyl with the alkyl substituent being, for example, methyl, ethyl, propyl, butyl (especially isobutyl), pentyl, branched hexyl and heptyl; cycloalkenyl, for example cyclohexenyl? aryl, for example, phenyl and phenyl substituted by, for example, 1-2 alkyl, alkoxy or alkylthio groups, for example methylthio; fluorine, chlorine; alkoxy, for example, methoxy, isopropoxy; aralkoxy for example benzyl-30 oxy? cycloalkoxy, for example cyclohexyloxy; aryloxy, for example, phenoxy and phenoxy substituted by 1 or 2 fluorine or chlorine atoms; alkylthio for example methylthio, ethylthio, propylthio and n-butyl-800 6 49 7 '2 thio; arylthio for example phenylthio? aryl (dialkoxy) methyl or aryl (alkylenedioxymethyl); N-alkyl-N-arylamino wherein the aryl group is, for example, phenyl or phenyl substituted by, for example, 1 or more fluorine or chlorine atoms; two Q groups together form a heterocyclic ring, for example benzofuryl or indolyl or Q taken together with 9H-carbazol-3-yl or naphthyl represents for example 6-methoxynaphth-2-yl.

Step 1) for preparing the compound of the formula 2 in which n and Q have the meanings indicated above is new.

Preferred compounds of the formula 1 are those wherein the formula is 7 or 8, wherein m is 0 or 1 and R 1 to R 5 are the same or different and hydrogen, alkyl, cycloalkyl, phenyl, suggest alkoxy, fluorine or chlorine. When m is 0, Q represents especially 2-fluoro-4-biphenylyl of the formula 9 and when ml is, especially 3-phenoxyphenyl of the formula 10.

Also preferred compounds of formula 1 include those wherein is methoxy and fluorine.

As stated previously, step 1) is a reaction which has not previously been applied. L. Farady, et al. In J. Organomet. Chem., 107, 107-116 (1969) reactions of phenyl, methyl or ethyl phenyl, mesityl or naphthyl magnesium bromide with ethylene in the presence of anhydrous nickel chloride, with a corresponding c (phenyl, methyl or ethylphenyl, mesityl, or naphthylethylmagnesium bromide is obtained, however, the preparation of the compounds of formula 1 or 2 by inserting an ethylene residue into the substituted arylmagnesium bromide of formula 3 is not described therein.

The invention further relates to a process for preparing a compound of the formula 1 ", wherein n is an integer from 1 to 4 and Qj is the same or not and hydrogen, alkyl of 1 to 4 carbon 8 00 6 49 7 3 atoms, cycloalkyl, alkyl, substituted cycloalkyl and cycloalkenyl by a) reacting a compound of the formula 3 "and ethylene in the presence of a catalyst in tetrahydrofuran, 5 tetrahydropyran or 2-methyltetrahydrofuran and preferably a hydrocarbon co-solvent and b) carboxylation of the compound of formula 2 "formed in step a to form the compound of formula 1".

Examples of groups designated for Qj include those listed for Qj.

Step A) for preparing the compound of formula 2 "is a new improvement. The use of the ethereal solvents or mixtures thereof and preferably a hydrocarbon co-solvent, results in unexpectedly higher yields.

Examples of compounds of formulas 1 "and 2" are those in which the 4-position is occupied and is alkyl, for example isobutyl, cycloalkyl, for example cyclohexyl, or cyclohexenyl.

Particular preference is given to compounds in which 20Q of isobutyl is in the 4-position.

The above article by L. Farady et al. Reports the ethylene addition to phenyl or an alkyl substituted phenylmagnesium bromide in the presence of anhydrous nickel chloride. However, there is no unexpectedly better yield by using said ethereal solvents alone or, preferably, in combination with a hydrocarbon co-solvent.

The carboxylation of Grignard reagents in both step 2) and step B) to form carboxylic acids is known. See the article by Finkbeiner et al. In J. Org. Chem., TT_, 3395 (1962) which describes the reaction of styrene and propylmagnesium bromide in the presence of titanium tetrachloride to form h-phenethylmagnesium bromide, which is then reacted with CO 2 to form hydratopeic acid; and the article by L. Farady 35 et al. in J. Organometallic Chemistry 28, 159 (1971), which describes a similar reaction with nickel chloride (NiCl 2).

However, there is no question of a reaction of ethylene and an arylGrignard reagent of the formula 3 "in said ethereal solvents and preferably with a hydrocarbon co-solvent according to the invention.

The arylmagnesium bromides of formulas 3 and 3 "are commercially available or can be prepared in various ways described in the literature. For example, U.S. Pat. No. 2,452,154 discloses a bromination of organic compounds which is particularly suitable for preparing starting compounds of the formula 3 ". The use of a mixture of bromine and chlorine is of particular advantage in this bromination.

When the acid of the formula 1 or 1 "in the aryl group contains a functional group which is itself reactive for the Grignard compound, it is usually necessary to protect this functional group before forming the Grignard compound, for example with groups, which can be removed by treatment with an acid.

In the reaction of an arylmagnesium bromide of the formula 3 or 3 "and ethylene in the presence of a catalyst according to the invention, the 2-arylpropionic acids are advantageously obtained.

The invention further relates to two improved coupling methods for preparing biaryl compounds of the formula IV wherein R'j and R'2 are the same or different and hydrogen, halogen, alkoxy with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, nitro, alkyl with 1 to 4 carbon atoms, cycloalkyl with 4 to 30 carbon atoms, phenyl, cyano or. represent a compound of formula 11 wherein x is an integer of 1 or 2, T is hydrogen or alkyl of 1 to 4 carbon atoms, and T 'represents individual alkyl of 1 to 4 carbon atoms or two groups of T' together form a cyclic diester, and 800 6 49 7 5 R 'and R'4 are the same or different and hydrogen, hydroxyl, halogen, nitro, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, aryloxy-carbonyl, phenyl, cyano or cycloalkyl of 4 to 7 carbon atoms 5, wherein a compound of the group of the formula 5 ^ is coupled with a compound of the formula 6 ^ wherein R '^ through R' ^ have the meaning indicated above. In the preferred improved coupling reaction, the compound of formula IV is reacted with a metal nitrite in the presence of a compound of formula and an acid in an aqueous or non-aqueous medium. In particular, the compound of the formula 5 ^ and the acid are added simultaneously to a mixture of metal nitrite and the compound of the formula 6 ^.

The other coupling method according to the invention for the preparation of the biaryl of the formula 6 ^ comprises the reaction of the compound of the formula 5 ^ and the compound of the formula by separate and simultaneous addition of the compound of the formula 5 ^ and a alkyl nitrite on the compound of formula 6j.

Examples of cyclic diesters include 2,2-dialkyl-1,3-dioxan-4,5-dione with in the alkyl radical 1 to 4 carbon atoms with preference for 2,2-dimethyl-1,3-dioxane-4 , 6-dion.

The alkyl radical in the alkyl nitrite contains 1 to 6 carbon atoms and includes methyl, ethyl, propyl, butyl, pentyl, and hexyl and isomers thereof.

Preferred compounds prepared by the coupling methods include those for the preparation of compounds of the formulas 1 and 2, such as bromides, from which the arylmagnesium bromides of the formula 3 can be prepared, for example 2-fluoro-4-biphenylyl bromide. Other preferred compounds are biaryl compounds of formulas 12 and 13 wherein T 'has the meaning indicated above.

The coupling methods described above are an unexpected improvement on the known Gomberg or Gomberg-Bachmann 800 6 49 7 6 reaction discussed by March in Advanced Organic Chemistry: Reactions, Mechanisms and Structure, biz, 550-551, 1968 (McGraw- Hill, Inc.). March reports, however, that "yields are not high (usually under 40%) because of the many side reactions undergone at diazonium salts," which are described here as intermediates, Cadogan in J. Chem. Soc. biz. 4257 (1962) the use of pentyl nitrite as a diazotizing agent thereby increasing the yield of said biaryl compounds. In other publications such as Dutch patent application 65.00865 10 C.A. 64, 5005e (1966) and U.S. Patent 3,992,459 disclose various coupling reactions based on the Gomberg or Gomberg-Bachmann reaction. However, there is no mention of the improvement thereon according to the invention which increases the birayl yield.

The yield improvement can probably be attributed to this that the formation of diazonium salt intermediates is limited so that side reactions leading to loss are avoided. This assumption is supported by the fact that no precautions are needed to avoid explosive decomposition of diazonium salts during the preparation and handling of large amounts of the reaction mixtures. This makes the coupling methods according to the invention advantageous over known methods.

One of the arylpropionic acids of formula 1 is known to be an important non-sterol anti-inflammatory agent, the / fluoro-biprofen or 2- (2-fluoro-4-biphenylyl) propionic acid. To prepare this compound by the process of the invention, 4-bromo-2-fluoroaniline is required as the starting compound. The invention also provides an improved preparation method for 4-bromo-2-fluoroaniline by reacting 2-fluoroaniline with a brominating agent, preferably dibromantine (1,3-di-bromo-5,5-dimethylhydantoin) in dimethylformamide or dimethylacetamide as a solvent . Nearly quantitative results with unusually high selectivity in the 4-position are unexpectedly achieved with dibromantine in dimethylformamide. The bromination of 2-fluoroaniline is described in 8 00 6 49 7 7 U.S. Patent 3,987,057 with reference to J.B. Wommack et al., J. Het. Chem., 6, 243 (1969). That 4-bromo-2-fluoroaniline is a suitable starting compound was first reported by K. Kuroda et al. In Nippon Kagaku Kaisha, 1876 (1973) 5 (Chem. Abstr., 78, 43571q (1973)). However, no mention is made of the improvement according to the invention. In view of the above-mentioned new steps, the process according to the invention as a whole constitutes a new synthesis for the preparation of the aryl propionic acids, in particular with the formula 1 'by 10 1) coupling a compound of the formula 5j' with a compound of the formula 6 'to form a compound of the formula 4', 2) forming a compound of the formula 3 'from the compound prepared in step 1); 3) preparing a compound of the formula 2 'by reacting the compound of the formula 3' from step 2) and ethylene in the presence of a catalyst and 4) carboxylating the compound of the formula 2 'to form a compound with the formula 1 '.

Obviously, the coupling step 1) is not limited to the previously described embodiment. For example, similar conditions as described in U.S. Patent 3,992,459 may be employed to react the compounds of formulas 5j 'and 6j'. These conditions include the use of copper or copper salt.

Important is Example 5, in which 2,4-difluoro-aniline is replaced by 4-bromo-2-fluoroaniline. However, the recovery and / or removal of the copper has some drawbacks. However, any of the coupling reactions described in said U.S. Pat. No. 3,992,459 30 may. be modified when the reaction is carried out in the presence of copper.

Scheme A shows a total synthesis of the preparation of the preferred compound (2- (2-fluoro-4-biphenyl) -propionic acid (flurbiprofen)).

In addition to the benefits of the reaction of arylmagnesium 8 00 6 49 7 8 sium broride, especially 2-fluoro-4-biphenylylmagnesium bromide, and ethylene in the presence of a catalyst, and unexpected yield increase in the new coupling reactions, the total synthesis according to the invention for the preparation of flurbiprofen 5 with 2-fluoroaniline as starting compound also has economic advantages.

In the known synthesis, 2-aminobiphenyl compounds are used, which may be mutagenic. The use of such intermediates is avoided in the synthesis of the invention.

Scheme B shows a preparation method for the compounds of formulas 1, 1 ", 2 and 2".

U.S. Patent 3,959,364 discloses the use of the same kind of arylmagnesium bromides as those of formulas 3 and 3 "for the preparation of arylpropionic acids by reaction with a salt of 2-bromopropionic acid. The yield of the Grignard reaction described therein is however low while using more expensive reagents.

Steps 1) and A) in which ethylene is reacted with Grignard reagent are carried out in a manner usual for 20 Grignard reactions, for example in an anhydrous medium. The reaction is generally carried out at a temperature of 0 ° C to the boiling point of the solvent. In general, however, the mixture of Grignard reagents is cooled to about -20 ° C during the addition of the reactants, and the temperature is allowed to rise to room temperature.

A catalyst is required to carry out the reaction of aryl-Grignard reagent and ethylene. Ziegler-Natta catalysts (when the reaction conditions have been changed to prevent polymerization) are effective, especially anhydrous nickel salts. While most nickel compounds are catalytically active to some degree, nickel chloride or nickel bis (acetylacetonate) is preferred.

It has further been found that by partial reduction of the nickel catalyst by a pretreatment, the activity is unexpectedly increased. 8 00 6 49 7, 9

The pretreatment may consist of adding 0-5 mol equivalent of an alkyl aluminum compound, for example triisobutyl aluminum, diethyl aluminum chloride or bromide, triethyl aluminum or ethyl aluminum dichloride to the nickel salt 5 in an ether or tetrahydrofuran solvent in an inert atmosphere for 0.5-3 hours. Another pretreatment consists of the reaction of 2 moles equivalent of diisobutylaluminum hydride and anhydrous nickel bis (acetylacetonate) at -30 to 0 ° C, in particular in step 1), The yields of steps 1) and A) are increased by evacuation of ethylene after absorption by the Grignard reagent. The reaction is carried out by saturating the reaction mixture with ethylene under a pressure of about 300-400 kPa (3-4 at) with vigorous shaking or stirring until no more ethylene is absorbed.

The yield of step 1) and step A) can be further increased by adding ethyl magnesium bromide to the reaction mixture after no more ethylene is absorbed.

It has been found that in step 1) the absorption of ethylene takes place in an ether as a solvent such as di-n-20 butyl ether or, preferably, diethyl ether. No or virtually no reaction occurs in a reaction mixture containing tetrahydrofuran, methylene dichloride, 1,2-dimethoxyethane or a mixture of equivalent amounts of diethyl ether and toluene as a solvent.

In contrast, in step A), an unexpectedly high yield is obtained upon absorption of ethylene in tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran and mixtures thereof or, preferably, one of these ethers in combination with a hydrocarbon cosolvent such as toluene or hexane, and the yield in diethyl ether, dioxane, 2,3-dimethyltetrahydrofuran, di-n-butyl-ether, diglyme or n-butyl ethyl ether, n-butyl methyl ether, dimethoxy methane, 2-methyltetrahydrofuran or 4-methyl dioxolane as solvent is low. Since 2-methyltetrahydrofuran is expensive, tetrahydrofuran is preferably used as the solvent.

However, it has further been found that when using hydrocarbon co-solvents such as toluene or hexane, the formation of unwanted dimer by-products in step A) is reduced so that the yield of the desired product of the formula 2 "increases. The ether to cosolvent volume ratio is generally 1: 1 to 3.5: 2, and preferably 1: 1.

- Reactions similar to those described above can be carried out replacing bromine in the compounds of formulas 3 and 3 "with chlorine or iodine. Similar conditions are applied with appropriate changes depending on the reactants and when the products with the Formulas 2 and 2 "are carboxylated, acidified and recovered as the compounds of formulas 1 and 1" as described below.

The mixture obtained in step 1) or step A) is cooled to a temperature between + 10 ° and -30 ° C for carboxylation in step 2) and step B), treated with dry carbon dioxide (CO 2) and then acidified with, for example, hydrochloric acid. The organic phase is extracted with water and weakly alkaline solutions, for example from sodium or potassium hydrogen carbonate. The compounds of the formula 1 or 1 "are separated from the combined aqueous extracts and purified in the usual manner, for example by extraction, evaporation, distillation, crystallization or chromatography.

According to another aspect of the invention, the compounds of formula 2 and 2 "are prepared by reacting a styrene derivative of formula 4 and 4" and ethyl magnesium bromide as shown in reaction scheme C, wherein n, Q and all the have the meaning indicated above, under the optimum reaction conditions described previously;

Although Finkbeiner et al., Supra, describes an exchange reaction of olefins, for example styrene, with a Grignard-30 reagent, his article does not suggest the novel method of the invention in which compounds of formulas 4 and 4 "are reacted with ethyl magnesium bromide in the presence of a nickel catalyst.

The reaction of the compounds of the formulas 35 and 4 "and ethyl magnesium bromide in the presence of a catalyst is generally carried out under the conditions described for step 1) and step A).

The compounds of the formula IV and IV "are preferably prepared as follows. A solution of the compound of the formula IV in benzene is added simultaneously with an acid to an aqueous mixture of an excess compound of the formula VI and solid or sodium or potassium nitrite dissolved in water The ratio of the compounds of the formula 5 ^ to 6 ^ is between 5:10 and 1:10. The acid may be an inorganic acid such as sulfuric acid, or an organic acid such as acetic acid monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, benzoic acid or methanesulfonic acid.

The temperature of the reaction mixture is between 25 ° C and the boiling point of the mixture, preferably for the higher temperatures within this range. The mole. The ratio of acid and sodium or potassium nitrite to the compound of the formula 5 ^ is 1: 1 to 4: 1 and preferably 2.5: 1. In a particularly preferred embodiment, the compound of formula 5 ^ and acetic acid are added dropwise to a mixture of the aqueous or non-aqueous metal nitrite and the compound of formula 6 ^. It is recommended to stir for 2-18 hours at the preferred temperature after the addition. The product of the formula is separated by cooling the reaction mixture, washing and evaporating or distilling. Preferably, the reaction mixture evaporated, extracted with hexane and washed with 85% sulfuric acid. The crude product can be used without purification to prepare the arylmagnesium bromide of the formula 3. However, since nitro compounds can be formed as by-products, it is recommended to reduce the reaction mixture with iron in acetic acid or sodium dithionite, so that these by-products amines are converted so that they can be easily removed from the product by acid washing. The conditions for the reduction of the nitro compounds are described by S.R. Faudler et al., In "Organic Functional Group Preparations," I Vol. 1, Academy Press, New York, 1968, p. 339.

35 When the coupling reaction under non-aqueous | 800 6 49 7; t 12 conditions is carried out with solid metal nitrite, it is recommended to add an adsorbent for water, such as anhydrous magnesium, sulphate, silica gel or Celite ®. Since potassium nitrite gives a higher yield in this reaction than 5 with sodium nitrite, it is preferred.

It has been found that in addition to the above-mentioned acids which can be used in this reaction, hydrofluoric acid and fluoroboric acid (HBF2) are active in the aqueous biphasic reaction mixture. Fluoroboric acid (HBF2), however, gives a particularly high and unexpected yield. When using sulfuric acid, a 10% solution is preferred.

For preparing the preferred 4-bromo-2-fluorobiphenyl compound of the formula IV, the temperature of the coupling reaction is 25-80 ° C, preferably 60 ° C.

The alternative coupling reaction is carried out with an alkyl nitrite instead of sodium nitrite in the absence of water. Thereby, a solution of the compound of the formula 5 ^ in excess of benzene is reacted with alkyl nitrite, for example isoamyl nitrite, in the presence of the compound of the formula at 20-80 ° C for 5-20 hours. Preferably, isoamyl nitrite and a solution of the compound of the formula 5 ^ in benzene are each added dropwise and simultaneously in about 20 hours to an excess of the compound of the formula 6 ^ with the temperature between 25 ° C and the boiling point of the solvent is kept, preferably at about 65 ° C.

The product of formula IV is treated with a reducing agent and separated as described for the preferred coupling reaction with metal nitrite.

As already mentioned, any of the described coupling reactions can be carried out in the presence of copper.

Particular preference is given to the use of the non-aqueous medium with sodium or potassium nitrite containing copper. The copper can be copper powder or a copper salt. When using copper powder, however, reaction conditions are applied such that a copper salt is formed in situ. The use of solid sodium or 8 00 6 49 7 β 13 potassium nitrite in a non-aqueous acidic medium containing copper has not been previously described.

The bromination of 2-fluoroaniline described previously is generally carried out by adding a solution of brominating agent dropwise to a solution of 2-fluoroaniline under conditions described by J.B. Wommack et al. In J. Het. Chem., 6, 243 (1969) (see above). Temperatures from 0 ° to -50 ° C, preferably -23 ° to -34 ° G, are required to achieve selective 4-position bromination with minimal formation of digrominated product. Preferred brominating agents are N-bromamides and N-bromimides, and in particular dibromantine. Preferred solvents are dimethyl formamide (DMF) and dimethyl acetamide and especially dimethyl formamide. With these solvents unexpectedly high yields and an unusually high selective bromination in the 4-position are achieved. In addition, suitable solvents are formamide, N-methylformamide, dioxane, di-glyme in ethylene chloride, and benzene. The use of benzene has the advantage that the reaction mixture can be used for the coupling reaction without further purification. The brominating agent can also be prepared in situ, for example N-bromoacetamide in dimethylformamide.

The same advantages are achieved with corresponding chlorinations of 2-fluoroaniline with the preferred solvents.

The 4-bromo-2-fluoroaniline formed can be conventionally obtained from the reaction mixture, for example, by extraction, chromatography or distillation.

Vobrbefeld I

2- (2-Fluoro-4-biphenvlyl) propionic acid of the formula 1 '.

30 A. 4-tBromo-2-fluoroaniline of the formula 5 '.

To 36.5 g (0.125 mol, based on a purity of 97.7%) 1,3-dibromo-5,5-dimethylhydantoin (dibromantine) under nitrogen in a dropping funnel is added 37.5 ml of DMF.

The mixture is stirred until the solids dissolve, after which 800 6 49 7 14 the light yellow solution is added dropwise over 55 minutes to a solution of 24.1 ml (0.250 mol) of 2-fluoroaniline in 30 ml of DMF, which is dissolved with solid carbon dioxide in acetone is kept at -34 ° to -23 ° C. The dropping funnel is rinsed with 5 ml of methylene-5 chloride, which is also added to the reaction mixture. The reaction mixture is poured into a separatory funnel containing 27 ml of methylene chloride, 128 ml of heptane, 11 g of 50% NaOH and 120 ml of water. The separated aqueous layer is extracted with 50 ml of 20% methylene chloride in heptane and the combined organic extracts are washed with 3 x 100 ml of water. After evaporation of the organic solution to a constant weight, 46.4 g (98% of theory) of an oil are obtained with the following composition (gas liquid chromatography): 6-bromo-2-fluoroaniline: 94%; 2-fluoroaniline: 0.2%? 2-bromo-6-fluoroaniline: 0.3%; 4,6-dibromo-15 2-fluoroaniline: 0%.

Instead of dibromantine, N-bromoamides or imides such as N-bromoacetamide or N-bromosuccinimide can be used as brominating agents. Dibromantine is preferred.

B. 4-Bromo-2-fluorobiphenyl of the formula 4 '.

1) Sodium nitrite method with water.

A solution of 96 g (0.50 mol) of crude 4-bromo-2-fluoroaniline and 60.0 g (1.0 mol) of glacial acetic acid in 100 ml of benzene is added dropwise over 7 hours to a mixture of 69.0 g of 25 (1.0 mol) sodium nitrite, 69 ml of water and 700 ml of benzene, which is kept at 65 ° C. The mixture is then stirred under a nitrogen atmosphere at 65 ° C overnight (12 hours). The cooled mixture is washed twice with 400 ml of 1N hydrochloric acid, then refluxed overnight (13 hours) with 20 g of 30 (0.36 mol) iron powder, 250 ml of methanol and 150 ml (1.8 mol) concentrated hydrochloric acid. The resulting solution is cooled and the benzene layer is washed with 490 ml of water and evaporated at 40 ° C / 40 mm Hg. The resulting dark oil is distilled under a reduced pressure of 10 mm of mercury to give 64.6 g (51.5%) of 4-35 bromo-2-fluorobiphenyl as total distillate with a boiling point of 800 6 49 7 15 about 132-141 ° C / 8 mm of mercury. The product crystallizes on seeding.

Variations on the sodium nitrite method for preparing 4-bromo-2-fluorobiphenyl of the formula 4 ^ yield corresponding results as shown in Table A.

8 00 6 49 7 16 I τί ΓΟ

Dl O O 03

P WW

1 O1 O1 0

C £ £ d) O

<d. “P Tl -O M O1 (0 P P d) £ E 0 H Μ Μ Ό 0 Cl 0>> # Tl

OS Μ M 0 P

Φ φ g O 0 Q, M

Tue .0 P 4-1>

p (Ö (0 3 M

M 2 =! Ï O dj

Cl P

> CM CN UI (8 O ill i r- r- i i ri s p w

Di

C

φ <#> WCNro Cl (* l ¢ 1 Ί ui IN

M minin inin invfiinco

Xi c, 0 3 h 1 3 2 11 in in 3

OW

> DiC m n (* i n (\ m cm cm JT * dl C 0) 0 Ή h 6 O '3 n 0; ^

<EU OCO OO OOOI

d> vO ιβ i £> ιβ U? 1D Ifl in

ij E-ι O

fcl λ -

p3 p p p. I

<M 3 I - M HP OM- '

Eh 3 3 Μ M 3 13 3 W OM

3NO33033 <N03 N> d) 03Nl8NN K H 3 COPN0C80 0'- ΛΝ • η N .0 0 · η x! 0 τι W <#> 00 p 0 O π P p Ml P · <Γ · Η -η Ν Ο PP Ν d) Ρ Ν ti Ο ΜΡ «J Λ Ό Ν <8 Ε 3 <8 CC Ρ Ν ιβ - - to - - - —-ίο Μ Ρ 30 m in ο in ο ο ο ο cm 3 I ooooooo ^ rw

jg «—I ♦« -Η · —I (* ~ 4 I

Ο σ ', σι σι 0 σ 0 ο σι ν η · - * - «· d>» dJ »' 0 a S vDiCiO d) νΧ3 dJiCiCd)

Di σ ci

Di (p) ® CN p (p) (p) (p) ^ p) (cn) (p) C ^ · -) O «NO '" 7 go E m ld ld ld in ιηιηΟΦ r02E CN CN CN CN CM CN (NO Γ "·

g «-4 rH« r-4 «H *“ 4 «H

• H

dl

r-H

3 P

EO OOO OO o o o o ρρ ιηιηιη min ininuiin 0 E t 1 Ό

MP ιβ XI O Ό d) <P Di .0 P

O Cl _Q ppp pp pppp 8 00 6 49 7 17 2) Isoamyl nitrite method.

Solutions of 375 ml (325 g, 2.8 mol) of isoamyl nitrite and of 378 g (2.0 mol) of crude 4-bromo-2-fluoroaniline in 250 ml of benzene are added separately and simultaneously dropwise over 5 hours in 5 hours. 3500 ml of benzene with vigorous stirring in a nitrogen atmosphere at 65 ° C (water bath). The mixture is kept at 65 ° C overnight, then cooled, washed twice with 250 ml of water and evaporated. The dark oily residue is dissolved in 750 ml of methanol and 450 ml of strong hydrochloric acid and treated with 138 g (2.1 mol) of zinc granules which is added in small portions in about 6 hours. To complete this "reductive quality improvement", the solution is treated with 54 g (Γ, Ο mol) of fine iron filings for 0.5 hour. The color of the mixture becomes significantly lighter within 1 hour. The solution is diluted with 1 liter of water and 1 liter of Skellysolve B (mixture of hexane isomers) and the liquids are decanted from the remaining metals. The aqueous phase is extracted twice with 1 liter of Skellysolve B and 1 liter of water. The solution is then dried over anhydrous sodium sulfate and evaporated to give 389 g of 4-bromo-2-fluorobiphenyl 20.

The product is distilled under vacuum to obtain 282 g (56%) of 2-fluoro-4-bromodiphenyl, bp 137-155 ° C / 11 mm of mercury, which crystallizes on standing.

Variations on the alkyl nitrite method for preparing 4-bromo-2-fluorobiphenyl of the formula IV give similar results as indicated in Table B.

30 800 6 49 7 18 η οο I 'C> -ι Ο Μ (β φ W φ 4 ·) Ο Ό θ' Ό 10 Ë φ X Φ Ε Ε Ο Ο 'Ί * Ο tt -Π α ο C ΜΗ η w φ φ φ μ φ σ 'σ τ3 α> a £ Η Φ ΟΡΟ

P -C X QS X, G

φ tr -ρ φ> -μ ιη <β ιη φ

Ο Ό Η> Η tP

V

to σ c I φ *> ιη οο & Ρ οο οο

I XI

Ρ 3 13 ρ Ρ Φ Ό C 3 3 Ο (0 φ 3 3> σ ρ Φ c 3 <-J * <4 »Ο · Η Eh θ’ α ra co EU -η

I I I

EHO <d m

I I

P P

03 O P O P

0 3 0 3) 3 «Η 3 rH σ ω £ Ν £ n

03 O C O C

<· Ρ · η · Η -η

And Ρ -γΊ Ρ · γ4 p -Η -μ Ν + J Ν 3 0 - · <σ w ιΰ 3 ΐ Ν Ε> Χ ΙΟ Γ- Γ-

C C

Ο -Η Φ Φ (ΝΕ φ Φ S3 σ> σ 4-1 Φ Ή Ρ μ Ή Π Η -Η Ο θ ’’ ’ίρ I r- r- Ο

W.

«Μ φ rH ι-Η ί I ο ο Ρ Ε ιη ιη ο £ I Ό Ρ> Η <0X3 Ο φ Ο φ · - '> X) (Ν (Ν 800 6 49 7 19 C. 2- (2- Fluoro-4-biphenylyl) propionic acid of the formula 1 '.

The entire procedure is performed under nitrogen or a CH 2 CH 2 atmosphere and in dry equipment.

5 To 12.2 g (0.50 gram atom) of magnesium in 100 ml of anhydrous ether is added dropwise 15.6 g (0.083 mol) of 1,2-di-bromoethane. When the reflux of the reaction decreases, a solution of 104.4 g (0.416 mol) of distilled 4-bromo-2-biphenyl in 300 ml of ether is added dropwise over 2 hours. The mixture is then refluxed for 1 hour to complete the formation of the Grignard reagent. Afterwards, the mixture is cooled to -20 ° C and saturated with ethylene, after which 1.08 g (8.5 mmol) of anhydrous nickel chloride (NiCl 2) is added. The mixture is then allowed to come to room temperature under an ethylene atmosphere at a pressure of about 300-400 kPa (3-4 at) with vigorous shaking or stirring. After 0.5-2 hours at room temperature when no changes are observed in gas liquid chromatography, excess ethylene is thoroughly removed by alternate evacuation to 10 mm of mercury with vigorous shaking or stirring for 2-6 cycles. The mixture is then cooled to -10 ° C and treated with CC> 2 gas until heat generation has ended. After the mixture has reached room temperature, acidify with 150 ml of 6N hydrochloric acid. The organic phase is washed twice with 100 ml of water and then extracted with 4 100 ml portions of 25 lN potassium hydrogen carbonate solution. The combined aqueous extracts are washed four times with 50 ml of methylene chloride and then acidified with 40 ml of concentrated hydrochloric acid. The product is extracted twice with 50 ml of methylene chloride and, after drying with anhydrous sodium sulfate, evaporated to give crystal line crude 2- (2-fluoro-4-biphenylylpropionic acid of the formula 1 '(flur-biprofen) in a yield of 50-). 80% based on the starting biphenyl.

The product is recrystallized several times at 4 times its weight of 10-25% ethyl acetate in Skellysolve B (or heptane) using 5 wt% Pittsburgh Cal-800 6 49 7 20 carbon for decolorization during the final crystallization, using flurbiprofene in a yield of 34-54%, based on the biphenyl and with a melting point of 110-114 ° C.

In the preferred embodiment, the batch catalyst is prepared in an amount of 60 mmole by adding dropwise 0.83 ml (1.2 mmole) of a 25% solution of triethyl aluminum in hexane to a suspension of 164 mg (0.60 mmol) anhydrous nickel bis (acetylacetonate) in 2 ml anhydrous diethyl ether on a bath at a temperature of -14 to -35 ° C under a nitrogen or ethylene atmosphere, The mixture is stirred at the same temperature for 2 hours and then added to the arylGrignard solution as previously described at -20 ° C. The ethylene absorption in this embodiment is as fast as that with 3 mol% nickel chloride, which has not been subjected to alkyl-15 aluminum reduction beforehand. The yield of flurbiprofene is 82% (gas liquid chromatography).

Example II

2- (4-Isobutylphenyl) propionic acid of the formula 1 ".

20 A, p-Bromo-isobutylbenzene (MW, 213.1).

a) Without catalyst.

To a solution of 67.1 g (0.50 mol) isobutyl benzene (MW 134.2) in 125 ml of liquid sulfur dioxide, cooled at -32 ° C in a bath of solid carbon dioxide and acetone with a temperature A temperature of -45 ° is added in a nitrogen atmosphere in 13 min. 95.9 g (0.60 mol) of liquid bromine. The mixture is kept at about -33 ° C for 1 hour and treated with 25 ml of water after which it is allowed to come to room temperature under evaporation of sulfur dioxide and hydrogen bromide. The organic phase is separated from the small aqueous phase. The aqueous phase is diluted with 75 ml of water and extracted with methylene chloride. The methylene chloride solution is combined with the organic phase, washed with 25 ml of 20% sodium hydroxide solution and twice with a semi-saturated sodium chloride solution. The organic solution is dried over anhydrous calcium chloride and then concentrated in vacuo to give 107.5 g of a pale yellow oil of the following composition (determined by gas liquid chromatography): 1.4% starting isobutyl benzene, 5.1% o-bromoisobutylben-; benzene and 94.0% p-bromoisobutylbenzene. This represents a theoretical yield of 5% o-bromoisobutylbenzene and 95% p-bromobisobutylbenzene.

b) with iron powder as a catalyst.

This procedure is similar to that without a catalyst but is carried out at -50 ° to -60 ° C after the preparation of the catalyst at -7 ° C.

Bromine (2 ml) is added to a suspension of 1.39 g (0.025 gram atom, 5 mol-1%) of iron powder in 125 ml of liquid sulfur dioxide at -7 ° C. After 0.5 hour at -7 ° C, the mixture cooled to -66 ° C after which isobutylbenzene (67.1 g, 0.5 mol) is added. The rest of the bromine is then mixed in 6.5 minutes.

added to a total of 101.9 g (0.64 mol) of bromine keeping the reaction mixture at a temperature between -52 ° and -60 ° C. After a further 50 minutes at a temperature between -53 ° and -57 ° C, the reaction mixture is treated with 49 ml of water and then worked up as under a). The crude product yield is 106.7 g. It contains 0.16 g of isobutyl benzene, 5.9 g of ortho and 91.3 g of para-bromo isobutyl benzene. This represents a yield of bromoisobutylbenzene of 6% and of p-bromoisobutylbenzene of 93%.

The main difference from the embodiment a) lies in the bromination rate at the low temperature. Gas chromatographic analysis indicated that in run a) 5% starting compound was present after 1 hour at -33 ° C versus only 0.3% after 1 hour at -57 ° C in the present, indicating that pre-prepared ferribromide the bromination accelerates at low temperatures.

c) with antimony trichloride as a catalyst.

A mixture of liquid sulfur dioxide (20 ml), antimony trichloride (149 mg) and bromine (0.52 ml, 1.52 g, 9.5 mmol) of -30 ° C is cooled to -72 ° C (some solid ) and within 3 800 6 49 7 22 sec. treated with 1.57 ml (10.0 mmol) of isobutylbenzene. The mixture, containing a substantial amount of solid, is stirred at -69 ° to -72 ° C for 70 min after which the reaction is quenched with 1.2 g (10.9 mmol) of resorcinol. After the mixture has reached room temperature under evaporation of sulfur dioxide, it is extracted with hexane. The hexane solution is washed with aqueous sodium hydroxide and water, dried over anhydrous magnesium sulfate and diluted with hexane to a volume of 100 ml for gas chromatographic analysis. The product contains 16% isobutylbenzene, 4% p-bromobisobutyl-benzene and 89% p-bromobisobutylbenzene.

This and the following two embodiments serve to determine the reaction rates at -70 ° C in 65-70 min. The reactions are stopped by addition of resorcinol, which reacts almost immediately with the residual bromine. A reference 15 version without a catalyst gives 22% isobutylbenzene, 2% ortho and 74% bromoisobutylbenzene. The higher conversion in the present embodiment indicates that antimony chloride increases the reaction rate.

d) with bromine chloride as a brominating agent.

Bromine chloride (Dow, 1.12 g, 9.7 mmol) is condensed in a solid carbon dioxide tube and then diluted with 20 ml of liquid sulfur dioxide and cooled to -72 ° C. Isobutylbenzene (1.57 ml, 10.0 mmol) is added and the mixture is stirred at -70 ° C for 65 min after which the reaction is stopped with 1.2 g of 25 (,90.9 mmol) resorcinol. After work-up, the analysis shows that 8% iso-butylbenzene, 6% ortho and 83% para-bromobisyl butbenzene are formed. This means that the bromination with bromine chloride proceeds faster than with molecular bromine and the degree of ortho-bromination is slightly higher.

In a similar embodiment, however, where the BrCl solution in liquid sulfur dioxide is added to the isobutylbenzene in liquid SC 4 at -70 ° C, yields of 16%, 5%, and 80%, respectively, are obtained.

e) with N-Bromosuccinimide.

35 To a mixture of 1.78 g (10 mmol) N-bromo-800 6 49 7

I -J

23 succinimide (NBS) in 20 ml of -30 ° C liquid sulfur dioxide, 1.57 ml (10.0 mmol) of isobutylbenzene are added. The mixture is stirred at -30 ° C to -18 ° C for 65 min and then worked up as described above. Only 2% of isobutylbenzene and 88% of recovered starting isobutylbenzene are obtained, which indicates that at this temperature the reaction with NBS proceeds very slowly.

f) with N-bromoacetamide catalyzed by BrCl.

1.57 10 ml (10.0 mmol) of isobutylbenzene are added to a mixture of 1.39 g (10 mmol) of N-bromoacetamide in 19 ml of liquid sulfur dioxide at -70 ° C. The mixture is treated with a solution of 0.05 ml BrCl in 1.5 ml SO4, stirred at -70 ° C for 65 min and afterwards worked up as described above. Gas chromatographic analysis has shown that 62% isobutylbenzene, 1.5% ortho-bromoisobutylbenzene and 35% para-bromoisobutylbenzene are formed. This means that N-bromine compounds act as brominating agents when an acidic catalyst (equivalent to HCl) is added. The low temperature reaction in liquid SO 2 is catalyzed by iron powder or antimony trichloride, but these catalysts are not necessary for efficient bromination.

Bromine chloride is also an effective catalyst per se, achieving a conversion of up to 90% of the p-bromo isomer.

B. 2- (4-isobutylphenyl) propionic acid (ibuprofen) (see reaction scheme F).

A solution of 1.0 ml 1,2-dibromoethane in 10 ml anhydrous tetrahydrofuran (THF) is added dropwise over 5 min to 1.90 g (78 gram atom) of magnesium shavings in 10 ml THF. The mixture is stirred for 2 min. heated to reflux, then a solution of 12.85 g (60 mmol) of p-bromobutylbenzene in 20 ml of THF is added dropwise over 50 min. The resulting mixture is heated to reflux for 15 minutes to complete the reaction. After cooling to -20 ° C, ~ 240 mg of anhydrous NiCl 2 is added and the mixture is allowed to come to room temperature with vigorous stirring or shaking in an ethylene atmosphere at a pressure of about 300-400 kPa (3-4 at). After 0.5-2 hours 35 at a temperature up to 30 ° C when no more ethylene is taken up, 800 6 49 7 24 the mixture is shaken under a reduced pressure of 10 mm of mercury for 20 min (bath temperature 45 ° C) to completely expel excess ethylene from the solution. The mixture is then cooled to -15 ° C and treated with excess carbon dioxide. The product is recovered by acidification, extracting with 1N potassium hydroxide and re-acidification to obtain crude ibuprofen in 47% yield (gas liquid chromatography). Pure ibuprofen, mp 73-74 ° C, is obtained in 91% yield by recrystallization of the sodium salt in water followed by acidification. The numerous hydratropic acids that can be prepared by the methods of the invention are known as therapeutic agents. See, for example, Wong: Nonsteroidal. Anti-Inflammatory Agents Chapter 18, Annual Reports in Medicinal Chemistry, Part 10, Utility of hydratropic acids, Section IV - Metabolic diseases 15 and endrocrine functione (ed. Morland), biz. 172-181 (1975); U.S. Patents 3,624,142, 3,755,427, 3,865,949, 3,784,705 and 4,052,514. The substituted biphenylyl compounds prepared with the novel coupling reactions of the invention are also known as therapeutic agents or precursors.

The starting compounds can be prepared in a known manner or are commercially available.

Example III

Work-up flurbiprofene by distillation (preferred).

* An extract of crude acids from the hydrolysis and extraction of Grignard carboxylation in toluene containing 51.3 g of flurbiprofene (gas liquid chromatography), is evaporated and the residue is distilled in vacuo. The fraction boiling at 119-176 ° C (usually at 172-176 ° C) at a pressure of 0.4-0.5 mm mercury is collected (49.2 g, solidification) and recrystallized in a mixture of 25 ml ethyl acetate and 170 ml heptane (decolorization with 0.5 g Darco G-60). The yield of dried product is 44.6 g (87%) and the purity 98.4% (according to gas liquid chromatographic analysis).

35 800 6 49 7. 25

Example IV

Bromination of 2-chloroaniline.

A solution of 286 g (1.0 mole) of dibromantine 5 in 300 ml of DMF is added dropwise over 3 hours to a solution of 250 g (2.0 mole) of 2-chloroaniline in 235 ml of DMF, also with a bath of solid carbon dioxide in acetone at -30 to -40 ° C and is kept under nitrogen. The mixture is stored in the refrigerator at 0 ° C overnight and then examined by gas liquid chromatography for starting 2-chloroaniline. A small amount of 2-chloroaniline (about 2%) has not reacted and therefore 2.86 g (0.01 mol) of dibromantine in 3 ml of DMF is added in 3 min. To the reaction mixture cooled to -25 ° C . After the reaction mixture is brought to a temperature of 20 ° C, it is diluted to 1000 ml for gas liquid chromatographic analysis.

This shows that the yield of 4-bromo-2-chloroaniline is 99%. The DMF solution is shaken in a separatory funnel with a mixture of 96 g (1.2 mol) of 50% sodium hydroxide solution, 1.25 liter of a solution of 20% methylene chloride in hexane and 500 ml of water. The aqueous phase is extracted with 200 ml of 20% methylene chloride in hexane.

The extract solutions are washed successively with 500 ml of water each time and then combined and diluted with 300 ml of methylene chloride when the product begins to crystallize upon removal of DMF. The solution is washed with 500 ml of water and then concentrated in vacuo to a thick suspension. This is diluted with 450 ml of heptane and heated, the crystals dissolving and cooling with seeding allowed to yield a mixture of crystals and oil. This mixture is reheated, treated with 250 ml of water and seeded with cooling. The product now crystallizes out nicely and is washed with 300 ml of water and 250 ml of hexane at -20 ° C. After drying overnight at room temperature, 367 g (91%) of 4-bromo-2-chloroaniline with a melting point of 69- 71 ° C.

35 8 00 6 49 7 t, i 26

Example V

4-Bromo-2-chlorobiphenyl.

To a solution of 304 g (4.41 mol) of sodium-5 nitrite and 244 ml of water in 2.5 liters of benzene, in a nitrogen atmosphere and on a water bath at 62 ° C, a solution of 365 g is added dropwise over 8 hours. (1.77 mole) 4-bromo-2-chloroanline and 212 ml (3.71 mole) glacial acetic acid in 212 ml benzene. The dark mixture is stirred overnight. The bottom aqueous layer is removed and benzene is distilled off at normal pressure. The residue is mixed with 500 ml of methanol and 81.4 g of iron powder, after which 1.093 liters of concentrated hydrochloric acid are slowly added.

The mixture is heated to reflux for 5.5 hours, then diluted with 1.4 liters of hexane and 1.4 liters of water and allowed to cool. The resulting suspension is filtered over Celite washed with hexane. The hexane phase is washed with water, dried over anhydrous magnesium sulfate, stirred with 40 g of activated Pittsburgh carbon, filtered again and concentrated to constant weight (355 g). The Celite cake is extracted with acetone, which is removed by evaporation. The residue is stirred with a mixture of 200 ml of methylene chloride, 200 ml of 85% sulfuric acid and 300 ml of hexane. The organic phase is washed with 3 x 200 ml of 85% sulfuric acid, always back-extracting with 200 ml of hexane. The organic phases are finally washed with water and concentrated to yield 28 g of oil containing a substantial amount of product. The oil is combined with the previously obtained crude product (355 g) and chromatographed on 3 kg of silica gel with hexane. The fractions containing the product are collected, combined and evaporated to a constant weight.

Thus, a total of 292.9 g (62%) of 4-bromo-2-chlorobiphenyl is obtained as a colorless oil. The structure was confirmed by gas chromatography mass spectrometry. The mass spectrum shows a typical BrCl triad at 266 (M +), 268 (base peak) and 270.

8 00 6 49 7 35 27

Example VI

2- (2-Chloro-V 1,1,1-biphenyl-4-yl) propionic acid.

To a suspension of 3.8 g (0.156 gram atom) 5 magnesium shavings in 50 ml anhydrous ether is added a solution of 2.1 ml (24 mmol) 1,2-dibromoethane in a nitrogen atmosphere. When the reaction subsides, a solution of 32.4 g (121 mmol) of 4-bromo-2-chlorobiphenyl in 40 ml of anhydrous ether is slowly added over 2 hours, keeping the mixture at boiling temperature 10. The mixture is cooled to below -20 ° C in a Parr bottle and 470 mg of anhydrous nickel chloride are added. The bottle is then placed in a Parr apparatus and shaken in ethylene at a pressure of about 420 kPa (4.2 at).

The mixture is stirred vigorously for 15 minutes without heating, with the temperature rising to 26 ° C. Water is passed through the jacket to maintain the temperature at 28-30 ° C. After a total of 38 minutes, no more ethylene is taken up. The pressure is released and the mixture is shaken with occasional evacuation to keep the pressure under normal (vacuum of 0.07-0.56 mm mercury) for 0.5 hours. Then the mixture is cooled to about -13 ° C by passing coolant at -35 ° C through the jacket The bottle is pressurized with dry carbon dioxide gas to about 140 kPa (.1.4 at) and the mixture is shaken for about 0.5 hours, temperature rises to 20 ° C.

"The pressure is released and the reaction mixture ether is acidified with excess 1N HCl. The layer is separated, washed with 2 x 25 ml of water and extracted with sufficient 1M KOH to achieve a pH 10 for the aqueous layer. The organic phase is extracted with 25 ml of water and the combined aqueous phases are washed with 50 ml of ether. The aqueous extracts are acidified with excess 10% sulfuric acid and extracted with 150 and 25 ml portions of ether. Both extract solutions are combined, washed with 50 ml of water and passed through a cotton plug in a dry bottle.

The ether solution is diluted with anhydrous ether to 800 6 49 7 28 250 ml and stirred in an ammonia atmosphere for 0.5 h with the ammonium salt precipitating. After cooling the suspension in ice, the salt is collected, washed with ether and dried in a stream of nitrogen. Thus, 26.4 g (79%) of the ammonium salt are obtained as a granular, not entirely white, solid.

The ammonium salt is recrystallized in water containing a small amount of ammonia. The free acid, obtained on acidification of the ammonium salt, is recrystallized from a mixture of heptane and ethyl acetate. Thereby 10 18.4 g (58%) "chlorobiprofene" with a melting point of 134-136 ° C

obtained.

Example VII

4-Bromo-2-fluorobiphenyl.

A suspension containing 1.0 g (15 mmol) of copper powder, 12.5 g (76.5 mmol) of trichloroacetic acid and 125 ml of benzene is stirred at 23-26 ° C under nitrogen for 4.5 hours. After cooling to 6 ° C, 10.5 ml (78.5 mmol) of isoamyl nitrite is added. After standing for 1.5 min. A solution of 9.5 g (50 mmol) of 4-bromo-2-20 fluoroaniline in 50 ml of benzene is added dropwise to the suspension over 0.5 h, the temperature being between 8 ° and 17 ° ° C is held. When all is added, the green suspension is allowed to reach 25 ° C and stirring at 23-25 ° C overnight. The yield is 88.7% according to gas liquid chromatographic analysis.

25 8 00 6 49 7

Claims (19)

A process for the preparation of a biphenyl compound, characterized in that a compound of the formula wherein R * j and R * gelijk is the same or different, hydrogen, halogen, alkoxy of 1 to 5 carbon atoms, alkoxycarbonyl of 3 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, cycloalkyl of 4 to 7 carbon atoms, phenyl, cyano or a group of the formula Π where x is 1 or 2, T is hydrogen or alkyl with 1 to 4 carbon atoms and T 'alkyl of 1 to 4 carbon atoms or two T's together form a cyclic diester, with the proviso that when R 1 and R 1 represent alkyl, cycloalkyl, phenyl or cyano, they do not have to occupy the ortho positions with respect to the biphenyl bond, and R '^ and R' ^ are the same or not, hydrogen, hydroxyl, halogen, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to / m 4 carbon atoms, alkoxy-35 carbonyl with in the alkoxy radical 1 to 6 carbon atoms, aryloxycarbonyl, phenyl, cyano or cycloalkyl with 4 to 7 carbon To represent substance atoms, it is prepared by coupling a compound of formula 5j and a compound of formula 6j wherein the compound of formula 5 is reacted with a metal nitrite in the presence of the compound of formula 6j. A method according to claim 1, characterized in that the coupling reaction is carried out in the presence of copper powder. 3. Process according to claim 1, characterized in that the coupling mainly consists of the reaction of the compound of the formula 5j and an aqueous metal nitrite in the presence of the compound of the formula 6j and an acid. 4. Process according to claim 3, characterized in that the compound of formula 5j and an acid are each simultaneously added to a mixture of aqueous sodium nitrite and excess benzene compound of formula 6j, in amounts selected such that the ratio of sodium nitrite and compound of the formula 5 ^ 1: 1 to 4: 1 and the ratio of acid and compound of the formula 5 ^ 1: 1 to 4: 1. 5. Process according to claim 4, characterized in that the acid is sulfuric or acetic acid. A method according to claim 4, characterized in that the acid is fluoroboric acid. 7. Process according to claim 1, characterized in that the coupling mainly consists of the reaction of the compound of the formula 5 ^ and non-aqueous metal nitrite in the presence of the benzene compound of the formula 6j, an acid and magnesium sulfate. 8. Process according to claim 7, characterized in that the compound of the formula 5 ^ and the acid are each simultaneously added to a mixture of finely divided potassium nitrite and excess benzene compound of the formula 6 ^ in such selected amounts, that the ratio of potassium nitrite and compound of the formula 5 ^ 1: 1 to 4: 1 and the ratio of acid and compound 15 of the formula 5 ^ 1: 1 to 4: 1. Process according to claim 8, characterized in that the acid is fluoroboric acid (HBF 4). Process according to claim 8, characterized in that the acid is acetic acid. 11. A process according to claim 1 or 10, characterized in that a compound of the formula 4 '' in which R 1, R 1, R 1 and R 1, whether or not equal, represents hydrogen, chlorine, bromine or fluorine, wherein at least one of the symbols R 1, R 2, R 1 and R 1 which is not hydrogen is prepared. Process according to claim 11, characterized in that 4-bromo-2-fluorobiphenyl is prepared by coupling 4-bromo-2-fluoroaniline and benzene. 13. Process according to claim 11, characterized in that R 1 and R 1 each represent fluorine and R 1 and R 1 each represent hydrogen, so that the compound is 2-fluorophenyl-4-yl fluoride. Process according to claim 12, characterized in that the 4-bromo-2-fluoroaniline is prepared by reacting 2-fluoroaniline and a brominating agent in dimethylformamide and / or dimethylacetamide as a solvent. 15. Process for preparing a biphenyl-8 00 6 49 7 - / f compound, characterized in that a compound of the formula V, wherein R 1 and R 2, whether or not equal, is hydrogen, halogen, alkoxy with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, nitro, alkyl with 1 to 4 carbon atoms, cycloalkyl with 4 to 5 7 carbon atoms, phenyl, cyano or a group of the formula 11 wherein x 1 or 2, T represents hydrogen or alkyl of 1 to 4 carbon atoms and T 'represents alkyl of 1 to 4 carbon atoms or two T's together form a cyclic diester, and R' 1 and R '1, whether or not not equal, hydrogen, hydroxyl, halogen, nitro, 10 alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with in the alkoxy radical 1 to 6 carbon atoms, aryloxy-carbonyl, phenyl, cyano, or cycloalkyl of 4 to 7 carbon atoms, is prepared by coupling a compound of the formula 5 ^ and a compound of the formula 6 ^ wherein the compound 15 of the formula 5 ^ and an alkyl nitrite are added separately and simultaneously to the compound of the formula 6 ^, in amounts selected such that the ratio of the compound of formula 5 ^ and compound of the formula 6 ^ 1:10 to 5: 10, and that the temperature is 25-80 ° C. 16. Process according to claim 15, characterized in that the coupling consists of the reaction of the compound of the formula 5 ^ and an alkyl nitrite in which the alkyl group contains 3 to 8 carbon atoms, in the presence of the benzene compound of the formula 6 wherein the compound of formula VI and the alkyl nitrite are added separately and simultaneously to the benzene compound. 17. A process according to claim 15, characterized in that R '1, R' 1 and R 4, hydrogen and R '1, occupying the ortho position relative to the N 11 group, represent fluorine so that 4 are coupled. -bromo-2-fluoroapiline and benzene. Process according to claim 17, characterized in that the 4-bromo-2-fluoroaniline is prepared by reacting 2-fluoroaniline and a brominating agent in dimethylformamide and / or dimethylacetamide as a solvent. 19. Compounds, methods and compounds obtainable, obtained and used 800 6 497 5 and pharmaceutical preparations containing these compounds, insofar as they are pharmacologically active, 800 6 49 7