DE3046522A1 - HALOGENATION OF 2-FLUORANILINE - Google Patents

Description

i ·

The Upjohn Company , Kalamazoo, Mich. United States

Dec. 10, 1980

Halogenation of 2-fluoroani lin

Dr. K.M./bf

December 4, 1980. 41 535

130035/0598

Halogenation of 2-Fluorani1 in

The present invention relates to a novel process for the preparation of aryl propionic acid. At a Process variant, special Grignard compounds are carboxylated, which in turn catalyze products of a Reaction between the corresponding aryl magnesium bromides and ethylene are. In addition, the reaction is used to produce the respective Grignard reagent novel itself. There is also an improved procedure for making coupled aryl compounds disclosed which are useful as intermediates in the preparation of compounds which are pharmaceutical Have effectiveness. For example, certain biaryls can be used to produce certain Grignard compounds produce, from which in turn aryl propionic acids can be produced. Finally will another improved bromination reaction disclosed which gives high yields of 4-bromo-2-fluoroani1 in, which is then coupled with benzene and finally used to make the aryl magnesium bromide to produce, which is then reacted with ethylene to obtain the special Grignard compound, and finally the desired arylpropionic acid, namely 2- (2-fluoro-4-biphenyIyI) -propionic acid.

The present invention relates to a process for the preparation of a large number of 2-arylpropionic acids, which are well known to have valuable therapeutic properties, such as anti-inflammatory Activity.

- 1 Dr. K.M./bf - qnmiwnnQR

December 4, 1980 IJUUJö / Uoöe 41 535

According to the present invention, a method made available, which for the preparation of compounds of the general formula

(O) _n .

\ / COOH

serves, where in this formula η is an integer in the range from 1 to 4 and Q denotes substituents of the same or different nature and has the following individual meaning: 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, fluorine, chlorine, dialkylamino, substituted and unsubstituted pyridyl, piperidyl, furyl, N-alkyl-morpholine, N-alkylthiamorpholine, pyrrolinyl, pyrrolidinyl, pyrrolyl, thienyl and where 2 groups Q taken together form a heterocyclic ring, or Q has such a meaning that together with the group ^ y it is a 9H-carbazole-3 -yl group, or a substituted naphthyl group, by adding a compound of the general formula in step 1

II MgBr

manufactured by making a compound of the general formula

- 2 -130035/0598

MgBr 111

with ethylene in the presence of a catalyst and in step 2 the compound of the formula II, which in step 1 was carboxylated to give the compound of formula I.

With regard to the substituents Q, which have already been mentioned above, the respective meanings include, for example the following individual meanings: aralkyl means, for example, benzyl; Cycloalkyl means, for example a cycloalkyl group having 3 to 7 carbon atoms and preferably a cyclohexyl group; Alkyl substituted Cycloalkyl means, for example, a group in which the alkyl radical is a methyl group, ethyl group, Propyl group, butyl group (preferably isobutyl group), pentyl group, branched hexyl groups and Denotes heptyl groups; an example of cycloalkenyl groups is the cyclohexenyl group; Examples of aryl groups are phenyl groups and substituted phenyl groups, those with, for example, 1 to 2 alkyl groups, alkoxy groups or alkylthio groups such as methylthio groups; Fluorine or chlorine atoms; Alkoxy groups, such as methoxy group, isopropoxy group; Aralkoxy groups such as benzyloxy groups; Cycloalkoxy groups such as e.g., cyclohexyloxy group; Aryloxy groups such as phenoxy groups and substituted phenoxy groups, the are substituted, for example, by 1 or 2 fluorine or chlorine atoms; Alkylthio groups, such as the methylthio

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Group, ethylthio group, propylthio group and n-butylthio group; Arylthio groups such as the phenylthio group; Aryl (dialkyloxy) methyl groups or aryl (alkylenedioxy) methyl groups; N-alkyl-N-arylamino groups in which the aryl radical is, for example, a phenyl radical or a substituted phenyl radical which is substituted, for example, with 1 or more fluorine or chlorine atoms, and it is ensured that 2 substituents Q together can form a heterocyclic ring, for example a benzofuryl or indolyl ring, or Q is determined in such a way that, together with the substituent @) , it results in a 9H-carbazol-3-yl, naphthyl group, such as a 6- Methoxynaphth-2-yl group.

It should be noted that step 1 mentioned above, which serves to connect the general formula

(Q) n

II

MgBr

to produce, where in this formula η and Q are as defined above are, is itself a novel process.

Preferred compounds of the formula I are those in which the grouping (Q) n _vr __ _{v has the} following meanings:

130035/0598

ORiGSNAL INSPECTED

ΟΙΟ

where in these formulas η is 0 or 1 and R 1 to R _{5 are} identical to or different from one another and have the following meanings: hydrogen atoms, alkyl groups, cycloalkyl groups, phenyl groups, alkoxy groups, fluorine atoms and chlorine atoms. When m is 0, the particularly preferred moiety is 2-fluoro-4-biphenylyl of the formula

and when m is 1, the most preferred moiety is 3-phenoxyphenyl of the formula

Preferred compounds of the general formula I which have been mentioned above are those in which the substituent R _{5 is} a methoxy group or a fluorine atom.

As noted above, reaction step 1 is itself a reaction that we know no one had used it before. For example, L. Farady et al. in J. Organomet. Chem., 17, 107-116 (1969) the implementation of phenyl, methyl or ethylphenyl,

130035/0598

■ 2-

Mesityl or napthyl magnesium bromide with ethylene in the presence from anhydrous nickel chloride to the corresponding et-phenyl, methyl or ethylphenyl, mesityl or naphthylethyl magnesium bromide to obtain. However, the process for the preparation of the compounds of formula I or II by introducing an ethylene unit into a substituted aryl magnesium bromide of the general formula III according to the present invention not in that cited above Work revealed.

Another object of the present invention is a process for the preparation of a compound of the general formula

(QOn

^ tO N S

I "COOH

where in this formula η is an integer in the range from 1 to 4, and the substituents Q _{1 are} identical to or different from one another and denote hydrocarbons which are selected from the following group: hydrogen atoms, alkyl groups with 1 to and with 4 carbon atoms, cycloalkyl groups, alkyl-substituted cycloalkyl groups and cycloalkenyl groups, in which step A is a compound of the general formula

(Qi) n

II "

manufactured by making a compound of the general formula

130035/0598

«Mn

with ethylene in the presence of a catalyst in a solvent, which contains tetrahydrofuran, tetrahydropyran or 2-methyltetrahydrofuran, and preferably has a hydrocarbon solvent, reacts and in a step B the compound of formula II ", which was prepared in step A is carboxylated to give the compound of formula "I".

The substituents Qi as mentioned above include examples similar to those Groupings which were mentioned above for the Q substituents.

It should be noted here that step A for the preparation of the compounds of the general formula

II "

Includes improvements that were not previously known in the prior art, due to the Use of special ethereal solvents or mixtures thereof and preferably a hydrocarbon auxiliary solvent, thus giving unexpectedly higher yields and accordingly this process step itself is new.

Examples of compounds of the formulas I "and II"

- 7th

130035/0598

are those in which the substituent or one of the substituents Q, is in the 4-position and is alkyl groups such as an isobutyl group; Cycloalkyl groups such as a cyclohexyl group; or a cyclohexenyl group. Particularly preferred compounds are those in which Q _{1 is} an isobutyl group in the 4-position.

The work by L. Farady et al. describes the addition of ethylene to a phenyl or Alkyl substituted phenyl magnesium bromide in the presence of anhydrous nickel chloride, but it has now been found that an unexpectedly improved yield is obtained by the process according to the invention if use special ethereal solvents alone or, preferably, in combination with a hydrocarbon auxiliary solvent is used, and accordingly the method according to the invention differs from those by L. Farady et al ..

The carboxylation of the Grignard reagent, as described in steps 2 and B, as they are in the process steps already mentioned by addition of plastic dioxide Manufacture of carboxylic acids is well known in the art. Of particular interest as prior art to date, the work by Finkbeiner et al. in J. Org. formerly., 27, 3395 (1962), these authors styrene with propylmagnesium bromide in the presence of titanium tetrachloride convert, whereby they get # -phenethylmagnesium bromide, which is reacted with carbon dioxide to obtain hydratropic acid. L. Farady et al. describes in

130035/0 59 8

0. of Organometallic Chemistry 28, 159 (1971) a similar reaction with nickel chloride (NiCl ₂ ). However, the specific reaction of ethylene with an aryl Grignard reagent of the general formula III "in an ethereal solvent or, preferably, with the aid of a hydrocarbon cosolvent, as described in the present invention, is not shown.

If the appropriate aryl compounds, from which the ary! magnesium bromide can be produced, not be mentioned in the following as novel production methods in the present specification, these aryl magnesium bromides of the formulas III and III "are either prepared by known procedures, or they are commercially available, or they can be prepared by a variety of methods described in the literature are described. It should also be noted that the manufacturing processes mentioned in the present description for suitable precursors aryl compounds from which the aryl magnesium bromides of the formulas III and III "should not be viewed as limiting factors, but that also known manufacturing processes used for it can be. For example, a bromination of organic compounds is described in US Pat. No. 2,452,154, and especially those which are useful in preparing the starting materials of the compounds mentioned herein of formula III ". The use of a mixture of bromine and chlorine in this bromination is particularly advantageous.

If the acid of the general formula I or I "a

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is such in which the aryl moiety is a functional one Contains group which is itself reactive with the Grignard compound, it is usually necessary that this functional group is protected before the Grignard compound is made. Effective Protecting groups are well known in the art. These protecting groups can later be removed, and for example by acidification.

It is shown more clearly below that when an arylmagnesium bromide of the formula III or III "with ethylene in the presence of a catalyst according to the present invention, a 2-aryi propionic acid is prepared is achieved, a more economical synthetic route is achieved.

In addition, the present invention provides two improved coupling methods for making biaryl compounds the general formula

R ¹ .

available, where in this formula R ¹ and R ^ are the same or different from each other, and hydrogen atoms, halogen atoms, alkoxy groups with 1 to and with 6 carbon atoms, alkoxycarbonyl groups with 1 to and with 4 carbon atoms, nitro groups , Alkyl groups with 1

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130035/0598

up to and including 4 carbon atoms, cycloalkyl groups with 4 up to and including 7 carbon atoms, phenyl groups, cyano groups and groups of the formula

where in this formula X is an integer in the range of 1 or 2 and T is a hydrogen atom or an alkyl group having 1 to and including 4 carbon atoms, and where T ^{1 is} an alkyl group with 1 to and including 4 carbon atoms or two groups T ¹ together form a cyclic diester, and where R '~ and R ¹ . are the same or different from one another and are hydrogen atoms, hydroxyl groups, halogen atoms, nitro groups, alkyl groups with 1 to and with 4 carbon atoms, alkoxy groups with 1 to and with 4 carbon atoms, alkoxycarbony1 groups with 1 to and with 6 carbon atoms , Aryloxycarbonyl groups, phenyl groups, cyano groups and / or cycloalkyl groups with 4 to and including 7 carbon atoms mean, in this process the compound of the general formula

^V l

with a compound of the general formula

- 11 130035/0598

"ι

coupling, where in these formulas R ¹ to R 'are as defined above. In the preferred of the two improved coupling reactions, the compound of the formula V is reacted with a metal nitrite in the presence of the compound of the formula VIj and an acid in an aqueous or non-aqueous medium. The simultaneous addition of the compound of the formula V and the acid to a mixture of the metal nitrite with the compound of the formula is particularly preferred

In the second coupling process according to the invention, an improved production method for the abovementioned biaryl of the formula IV is achieved by using a process which consists in coupling the compound of the formula V with a compound of the formula VI by separating and at the same time the compounds of the formula V ₁ and an alkyl nitrite of the compound of the formula VI are added.

Cyclic diesters are 2,2-dialkyl-l, 3, dioxane-4,6-diones, in which the alkyl group has 1 up to and including 4 carbon atoms contains, and 2,2-dimethyl-1,3-dioxane-4,6-dione is preferred.

It should be noted here that the above-mentioned connections for the coupling process, which only two Have substituents per phenyl ring of the biaryl product,

- 12 130035/0598

are not intended to limit the invention to this bond class.

The alkyl nitrite is an alkyl compound with 1 to and with 6 carbon atoms and includes, for example Methyl, ethyl, propyl, butyl, pentyl and hexyl and their isomers.

Preferred and especially preferred compounds which are produced in the coupling process are, for example those used to prepare compounds of formulas I and II and, accordingly, groupings have, which have already been mentioned above, and so for example bromides, from which the aryl magnesium bromides of Formula III, such as 2-fluoro-4-biphenylyl bromide. Also particularly preferred Compounds which can be prepared by the process according to the invention are the biaryls of Formulas

F F

CH ₃

and F-

(CO ₂ T ') a

where in these formulas the substituent T ^{1 is} as defined above.

According to the coupling procedure mentioned above the well-known Gomberg or Gomberg-Bachmann reactions in unexpectedly improved, for example from March in Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, pp. 550-551, 1968 (McGraw-Hill, Inc.). March holds, however,

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130035/0598

that "the yields are not high (usually below 40%) are because · many side reactions are entered into by the diazonium salts ", which are described there as intermediates will. The use of pentyl nitrite as a diazotizing agent for increased yields of the said Biarylene describes Cadogan in J. Chem. Soc, page 4257 (1962). Newer references, such as the Dutch

Patent Specification No. (Application No. 6,500,865 from Jan.

July 1975); Chemical Abstract 64, 5005e (1966) and U.S. Patent 3,992,459 disclose several Coupling reactions that build on the work of Gomberg or Gomberg-Bachmann, however, are not in any This work proposed improvements according to the present invention, in which the yields of Biaryl compounds turn out to be unexpectedly high.

Although here made considerations about the mechanism which leads to the fact that the two according to the invention Processes provide improved yields, are not regarded as terminating, it is assumed that the formation of the diazonium salt intermediates is restricted, and accordingly the side reactions, which reduce the yields known from the prior art, can be prevented. This attempted explanation is strengthened by the fact that it has been found that the method according to the invention has an additional advantage offer that namely no precautionary measures are required are to explosive decomposition of the diazonium salt in the production and handling of larger quantities of Reaction mixtures are necessary. Accordingly, the coupling processes according to the invention are more unexpected

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130035/0598

Way advantageous over the prior art.

Among the aryl propionic acids which are the object of the present invention, there is not an important one steroid anti-inflammatory agent known as flurbiprofen or 2- (2-fluoro-4-biphenylyl) propionic acid is known. In order to use the inventive method Flurbiprofen To prepare, 4-bromo-2-fluoroaniline is used as the starting material is needed, and accordingly an improved manufacturing process for 4-bromo-2-fluoroaniline made available, which consists in reacting 2-fluoroaniline with a brominating agent, and Particularly preferred for this is dibromantine (1,2-dibromo-5,5-dimethylhydantoin), in a solvent which contains dimethylformamide or dimethylacetamide. Dibromantine in dimethylformamide unexpectedly gives almost quantitative results with an unusual one high selectivity for the 4-position.

U.S. Patent 3,987,057 shows that the bromination of 2-Fluorani1 is well known to the person skilled in the art is, and it is, for example, J.B. Wommack et al., J. Het. Chem., G, 243 (1969) cited. The first report that the 4-bromo-2-fluoroaniline is useful as a starting material, appears in K. Kuroda et al., Nippon Kagaku Kaisha, 1876 (1973); Chem. Abstr. 78, 43571q (1973). But is in these references fail to find anything of the improved mode of manufacture afforded by the present invention is made available.

Taking into account the above-mentioned novel manufacturing methods according to the invention, a complete Process that is not yet known according to the state of the art

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130035/0598

has been proposed to be given for the synthesis form arylpropionic acids, which is also according to the invention. Accordingly, the present invention provides a novel method of making a connection the general formula

available, which is characterized in that man

1.) an invention of the general formula

with a compound of the general formula

VI

couples, whereby you get a compound of the general formula

- 16 -

130035/0598

Br "

IV ₁ -

receives, and one

2.) a compound of the general formula

MgBr

III

from the compound made in step 1 by

3.) a compound of the general formula

Z \ - \ - J V4 _> \ MgBr

R ₁

II

prepared by reacting the compound of the formula III from step 2 with ethylene in the presence of a catalyst, and you

4.) the compound of the formula II ^{1 is} carboxylated, whereby the compound of the formula I ¹ is obtained, and where R ,, Rp> ^R 3 ^{ur |} d R _{4 are} all as defined above.

- 17 -

130035/0598

■ 30

Accordingly, the present invention also includes production processes or improved production processes for compounds which are used in the processes according to the invention for the production of aryl magnesium bromides, corresponding to the respective Grignard compounds, which are involved in the novel reaction Ethylene as described herein, and from which the preferred aryl propionic acids are obtained.

It should also be noted that the above step of the coupling reaction is not restricted to the process conditions according to the invention. For example, process conditions may be similar to those as cited in the US Patent No. 3,992, 459, used to implement the compounds V and VI ₁ ¹ ₁ 'to each other. These conditions include the use of copper or copper salt.

Of particular interest is Example 5 in which 4-Bromo-2-fluoroaniline is used in place of the corresponding reactant 2,4-difluoroaniline. However, it does arise certain drawbacks to copper reprocessing and / or its disposal, which makes a difference between the coupling reaction according to the invention for the preparation of the compound IV, and the reaction given in US Pat. No. 3,992,459. On the other Each of the coupling reactions given here can be further modified by putting the reaction in the presence of copper.

A preferred embodiment of the invention Process leading to a particularly preferred compound as mentioned above is as follows

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130035/0598

-at-

Formula scheme shown:

NH

I bromination

. NH ₂

Br

Mg

vr

IV

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130035/0598

III ¹

MgBr

Ethylene and catalyst

step

II ¹

step 2

- 20 -130035/0598

S3

The compound so produced is 2- (2-fluoro-4-biphenyIy I) propionic acid (flurbiprofen).

In addition to the advantages already discussed for the implementation of aryl magnesium bromide, especially of 2-fluoro-4-biphenylylmagnesium bromide with ethylene in the presence of a catalyst, and in addition to those already The improved yields mentioned in the novel coupling reaction are also significantly more economical Advantage in the production of Flurbiprofen if you use 2-FluoraniI in as a starting material in the invention Procedure used.

The previous syntheses used 2-amino-biphenyl compounds, which could be mutagenic. The process according to the invention avoids such intermediate products.

With regard to the above-mentioned novel process for the preparation of the compounds of the formulas I or I "and of formula II or II "result in the following formula schemes-

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130035/0598

examples:
(Q)

HgBr

Step 1

MgBr

MgBr

II "

Step B.

COOH

COOH

I "

It should be noted that U.S. Patent No. 3,959,364 discloses a use of an aryl magnesium bromide similar to the compounds of formulas III and III "of the present invention is disclosed, also at a process for the preparation of aryl propionic acids

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130035/0598

· Ο? 5 ·

by reaction with a salt of 2-bromopropionic acid. However, in the Grignard reaction, it is disclosed therein does not provide the advantageous yield and desirable use of less expensive reactants found, as is the case with the present invention.

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£ 6.

Steps 1) and A), in which ethylene is reacted with a Grignard reagent, are generally carried out carried out in the usual way as is the case for Grignard reactions, for example in an anhydrous medium. The reaction is usually carried out at a temperature from 0 ° to the boiling point of the solvent. Usually however, the mixture of Grignard reagent is cooled to about -20 C while adding the reactants and then allowed to warm to room temperature.

A catalyst is required to effect the reaction of ethylene with the aryl Grignard reagent. It will disclosed here that catalysts of the Ziegler-Natta type (when the conditions are changed in such a way as to allow polymerization to prevent) are extremely effective for this purpose. In particular, anhydrous salts of nickel are effective in the desired reaction. Although most nickel compounds cause the reaction to some extent, The preferred nickel salts are nickel chloride or nickel bis (acetylacetonate).

It has also been found that a partial reduction of the nickel catalyst by a

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Pretreatment causes a surprising increase in the effectiveness of the preferred nickel catalyst. A pretreated one Catalyst is particularly preferred. The pretreatment consists in the addition of 0 to 5 molar equivalents of alkyl aluminum compounds, for example tri-isobutylaluminum, Diethyl aluminum chloride or bromide, triethyl aluminum, Ethyl aluminum, dichloride, to the nickel salt in an ether or tetrahydrofuran solution, under an inert atmosphere for 0.5 to 3 hours. Equally effective pretreatment conditions include the reaction of 2 molar equivalents Diisobutylaluminum hydride with anhydrous Nickeibis (acetylacetonate) at -30 to 0 C, and in particular in the above-mentioned reaction according to step 1).

The yields are greatly increased, both in step 1) and in step A) through the evacuation of the ethylene gas after the absorption of the ethylene in the Grignard reagent. The absorption is caused by the saturation of the reaction mixture with the gas below 3 to 4 atmospheres Pressure with vigorous shaking or stirring, and it is complete when the reaction mixture shows no further absorption of ethylene.

The yields are also influenced in an advantageous manner, in both steps 1) and A), by adding ethyl magnesium bromide to the reaction mixture, as described above, and also after the mixture shows no further uptake of ethylene.

It turns out in step 1) that the absorption of ethylene in an ether solvent, such as

- 25 130035/0598

'28 -

Di-n-butyl ether or diethyl ether, and preferably in diethyl ether entry. On the other hand, essentially no reaction occurs in a reaction mixture which contains tetrahydrofuran, Methylene dichloride, 1,2-dimethoxyethane or a mixture having equivalent amounts of diethyl ether and toluene as solvents. In contrast, it turned out that that in step A) the absorption of ethylene unexpectedly results in a high yield in an ether solvent results, as for example in tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran, mixtures thereof, or preferably one of the two ethers in combination with a hydrocarbon auxiliary sweetener such as, for example Toluene or hexane. In this reaction, on the other hand, only a negligible yield is obtained in diethyl ether, Dioxane, 2,5-dimethyltetrahydrofuran, di-n-butyl ether, diglyme, n-butyl ethyl ether, η-butyl methyl ether, dimethoxymethane, 2-methyltetrahydrofuran or 4-methyldioxolane. Because 2-methyltetrahydrofuran is more expensive, the preferred ether component of the solvent system for this reaction is tetrahydrofuran.

However, it has also been found that

the use of the hydrocarbon auxiliary solvent such as toluene or hexane, advantageously the Reduced formation of undesired by-products in the reaction of step A). Favorable conditions of ether to hydrocarbon in a solvent-cosolvent mixture range from 1: 1 to 1: 0 ratio. The use of the hydrocarbon cosolvent im Step A) brings about an unexpected benefit in that the formation of dimers is reduced, and accordingly the

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Formation of the desired product of Formula II "is increased, and accordingly a preferred volume ratio exists in the range from 1: 1 to 3.5: 2, with 1: 1 being particularly preferred.

Reactions similar to those described above can be carried out using the bromide compounds of the formulas III and III "are replaced by the corresponding chlorine or iodine compounds.

Similar conditions are used with appropriate modifications depending on the reactants and the reactants corresponding products II and II ", which are carboxylated and acidified, and whereby the compounds I and I" in a manner similar to that described below.

The mixture obtained from steps 1) and A) is cooled for carboxylation in Step 2) or step B), each at temperatures between + 10 C and -30 C. The mixtures are then with treated with dry carbon dioxide (CO) gas and then acidified, for example with hydrochloric acid. An organic phase obtained in this way is extracted with water and also with weakly alkaline solutions, such as, for example Sodium or potassium bicarbonate. The compounds of the formulas I or I ″ are isolated and from the combined aqueous Extracts from the corresponding steps 2) or B) isolated and purified according to customary procedures, i.e. for example by extractions, evaporation, distillation, crystallization, chromatography and the like.

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13 0035/0598

. ORSGlNAL INSPECTED

It should be noted here that a styrene-like Compound of the formula IV and IV "also with an ethyl magnesium bromide implemented under the appropriate optimal conditions described above can to obtain the desired Grignard reagent of the formula II or II "as follows:

+ H ₃ C-CH ₂ -MgBr

Catalytic

Ethylene and / or + ethylmagnesium bromide

MgBr

IV "

(Qi) n

+ H ₃ C-CH ₂ MgBr

NiCl ₂ catalyst

- ethylene and / or + ethylmagnesium bromide

II ¹¹

MgBr

being in these formulas

n, Q and Q- are all as defined above.

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• 3λ>

Although Finkbeiner et al., Already cited above, an exchange of olefins, for example Describing styrene with a Grignard reagent, he reports nothing about the novel according to the invention Process as shown above and that consists in that the compounds of the formulas IV and IV "with ethylmagnesium bromide in the presence of a nickel catalyst.

It should be noted that these reactions of the compounds IV and IV "with ethylmagnesium bromide in the In the presence of a catalyst, can generally be carried out using conditions such as those for the steps 1) and A) above.

The improved conditions for the coupling reaction according to the present invention are given above for the preparation of compounds of formula IV, and in general they are described in the following manner.

First, the preferred embodiments for the coupling reaction are described as follows: A benzene solution of the compound of the formula V .. is added simultaneously with an acid to the non-aqueous mixture of an excess of the compound VI ₁ with solid sodium or potassium nitrite. Alternatively, a benzene solution of the compound V. can be added simultaneously with an acid to a mixture of an excess of the compound of the formula VI and an aqueous solution of sodium or potassium nitrite. The ratio of the quantities of

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Compounds V ₁ to VI ₁ is in the range from 5:10 to 1:10. The acid can be a mineral acid, such as sulfuric acid, or an organic acid, such as benzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, methanesulfonic acid or acetic acid. The temperature of the reaction mixture is kept in the range between about 25 ° C. and the boiling point of the mixture. Temperatures in the higher part of this range are preferred. Molar amounts of the acid and the sodium or potassium nitrite to the amount of compound V are in the range of 1 to 4 times, and preferably 2.5 times are used. In a particularly preferred embodiment, the compound of the formula V and acetic acid are added dropwise to a mixture of the aqueous or non-aqueous metal nitrite in component VI. added. Stirring for 2 to 18 hours after addition is complete at the preferred temperature of the reaction is advantageous. The product of formula IV is isolated by cooling the reaction mixture, washing, evaporating, distilling or other conventional procedures. A particularly simple and preferred work-up method consists in evaporation and extraction with hexane and washing with 8 5 percent sulfuric acid. The crude product of the formula IV ₁ is obtained and further purification does not have to be absolutely necessary for the use of this product in the preparation of the arylmagnesium bromide of the formula III, which is further reacted by the process according to the invention. On the other hand, nitro compounds can occur as a by-product of this reaction, and so it is advantageous to reduce the reaction mixture by adding iron / acetic acid mixtures or sodium dithionite, thereby reducing these by-products.

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products are reduced to amines, so that these can be removed from the product by simply washing with acid. Conditions for the reduction of these nitro compounds are similar to those reported by S.R. Faudler et al., in "Organic Functional Group Preparations", Volume 1, Academic Press, New York, 1968, page 339.

When the coupling reaction is carried out under non-aqueous conditions with solid metal nitrite, is It is just as advantageous to add a water absorber, such as anhydrous magnesium sulfate, silica gel or Celite. In addition, the use of potassium nitrite instead of sodium nitrite is beneficial in these reactions, since it gives a higher yield and accordingly the use of potassium nitrite is one of the preferred conditions for the anhydrous coupling reactions.

In addition to the acids mentioned above for use in this reaction, it has been found that hydrofluoric acid in the two-phase aqueous reaction mixtures and fluoroboric acid are effective. However, fluoroboric acid (HBF ^) gives a particularly high and unexpected one high yield. If sulfuric acid is used, a 10 percent solution is preferred.

In the preparation of the particularly preferred 4-bromo-2-fluorobiphenyl compounds of the formula IV for the use in the subsequent reaction according to the invention Process as described herein, the preferred temperature for the coupling reaction is Range from 25 - 80 ° C and especially preferably at 60 C.

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The alternative coupling reaction, also outlined above, uses alkyl nitrites in place of sodium nitrite and is carried out in the absence of water. In this reaction, an excess solution of the compound of the formula V ₁ in benzene is reacted with alkyl nitrite, such as, for example, isoamyl nitrite, in the presence of the compound of the formula VI. at 20 - 80 ° C for a period of 5-20 minutes. In this embodiment of the present invention, isoamyl nitrite and a solution of the compound of the formula V ₁ in benzene are each added dropwise separately but simultaneously over a period of about 20 hours to an excess amount of the compound of the formula VI ₁ , while the temperature is in the range of 25 C to the boiling point of the solvent, and preferably works at a temperature of about 65 C. The product of formula IV ₁ is treated with a reducing agent and isolated in a manner as described above for the preferred coupling reactions using metal nitrites.

Finally, all of the coupling reactions described here can be further modified like this previously established by carrying out the reactions in the presence of copper. For example, the Use of a non-aqueous medium together with sodium or potassium nitrite, especially preferred when copper is present. The copper can be in the form of copper powder or a copper salt. However, if a copper powder is applied then the reaction conditions used ensure the production of the copper salt in situ currently. The prior art includes combinations of

- 3Z 130035/0598

Reaction conditions as disclosed here, namely the use of solid sodium or potassium nitrite in a non-aqueous acidic medium in which copper is also present, are not known. Accordingly, this particular coupling reaction itself is novel. The bromination of 2-fluoroaniline described above is generally accomplished by adding dropwise a solution of brominating agent to a solution of 2-fluoroaniline using conditions such as those described by JB Wommack, et al., J. Het. Chem., 6, 243 (1969) (see above). Temperatures from 0 to -50 ⁰ C, and preferably -23 to -34 ° C are necessary in order to obtain selective bromination in the 4-position and to obtain a minimum formation of dibrominated products. The brominating agent and solvent for the bromination of 2-fluoroaniline for use in the novel process of the present invention can be selected from those known in the art to be suitable therefor. However, the preferred brominating agents are N-bromamides or N-bromimides, with dibromantine, as already mentioned above, being particularly preferred. It has now been found that the preferred solvents are dimethylformamide (DMF) and dimethylacetamide, and DMF is particularly preferred. These preferred solvents give unexpectedly high yields and unexpectedly high selective bromination at the 4-position, and accordingly they give advantages not known in the prior art. Other other solvents can also be used, such as, for example, formamide, N-methylformamide , Dioxane, diglyme in ethylene chloride or benzene. One advantage to using benzene is that

- 33-130035 / 0598

the reaction mixture can be used in the coupling reaction as described herein without any further Cleaning is necessary. Another possible advantageous variation consists in the in situ preparation of the brominating agent, namely N-bromoacetamide in dimethylformamide.

The above-mentioned particularly preferred solvents also give the mentioned advantages in known ones corresponding chlorinations of 2-fluoroaniline.

The 4-bromo-2-fluoroaniline formed can be isolated from the reaction mixture by customary procedures, such as by extraction, chromatography, distillation or combinations of these procedures. In the the following examples all temperatures are given in ° C, the abbreviation ml means milliliter. The abbreviation glc means Gas liquid chromatography. The abbreviation g-at means gram-atoin.

In the following examples are preferred

Embodiments of the present invention described. Especially the production of 2- (2-fluoro-4-biphenylyl) -propionic acid, which is a particularly preferred compound according to the invention is described. It should be noted, however, that the idea of the invention is not restricted by these examples, which only selected preferred embodiments represent the invention.

Example 1: Preparation of 2- (2-fluoro-4-biphenylyD-propionic acid I ^!

A) Manufacture_yon_4-bromine; 2-fluoroaniline_V ^ _{: -}

To 36.5 g (0.125 mol, based on a content of 97.7%)!, S-Dimbrom-BjS-dimethyl-hydantoin ("Dibromantin")

- 3t-

130035/0598

is made under a nitrogen atmosphere using a dropping funnel 37.5 ml of dimethylformamide were added. The mixture is stirred until the solids have dissolved and then the light yellow solution is added dropwise over 55 minutes to a solution of 24 ml (0.2 50 mol) of 2-fluoroaniline in 30 ml Dimethylformamide added, which is kept at -34 to -23 ° C by means of a dry ice-acetone bath, added. Of the The dropping funnel is washed out with 5 ml of ethylene chloride, which is also added to the reaction mixture. The reaction mixture will Filled into a separatory funnel, which 27 ml of methylene chloride, 128 ml of heptane, 11 g of 50% sodium hydroxide solution and contains 120 ml of water. After the phase separation, the aqueous layer is washed with 50 ml of 20% strength methylene chloride extracted in heptane, and the combined organic extracts are washed three times with 100 ml of water each time. Evaporation the organic solution to a constant weight gives 46.4 g (98% of theory) of an oil. Gas chromatography analysis gives the following chemical yields:

4-bromo-2-fluoroaniline 94%

2-fluoroaniline 0.2%

2-bromo-6-fluoroaniline 0.3% 4,6-dibromo-2-fluoroaniline 0%

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

B) Production_of_4-Brom-2-fluorbigheny ^ _iy ^

(1) Sodium nitrite method with water.

A solution of 96 g (0.50 mol) of crude 4-bromo-2-fluoroaniline and 60 g (1.0 mole) of glacial acetic acid in 100 ml of benzene

- 35-130035/0598

is added dropwise over 7 hours to a mixture of 69.0 g (1.0 mol) of sodium nitrite, 69 ml of water and 700 ml of benzene added dropwise, and the mixture we ^ at 65 ° C held. The mixture is then stirred at 25 ° C. overnight (12 hours), a nitrogen atmosphere being created receives. The cooled mixture becomes 1 normal twice with 400 ml Washed hydrochloric acid and then heated to reflux conditions overnight (13 hours) together with 20 g (0.36 mol) of iron powder, 250 methanol and 150 ml (1.8 mol) of concentrated hydrochloric acid.

The resulting solution is cooled and the benzene layer is washed with M-90 ml of water and man evaporates at 40 ° C and a pressure of 40 mm of mercury a. The dark oil obtained in this way now becomes mercury at 10 Distilled pressure, whereby 64.6 g (51.5%) of H-bromo-2-fluorobiphenyl in the form of the entire distillate with a main boiling point of approximately 132-141 C at a pressure of 8 mm. The product crystallizes when inoculating.

Variations in the sodium nitrite process for making 4-bromo-2-fluorobiphenyl of Formula IV ^ result corresponding results as shown in Taoelle I.

- 36-130035/0598

TABEL example

NaNO NO

mmol

<i:

2 (2)

H ₂ O ml

acid
mmol

Encore
Temp, time

° C h

yield

Other mmoles

co ο ο cu cn ·>. ο cn co co

CO

1) a 1) b 1) C. 1) d 1) e

1) f

50 50 50

50 50

50

1) G 50 1) H 50 1) • 50

125

(2)

100

₇₉

<i)

6.9 105 acetic acid 60 6.9 105 benzene acid 60

6.9 100 dichloro-60 acetic acid

no acetic acid

100 methanesulfonic acid

6.9
not 100 acetic acid

100 (BF ₄ H)

(10% H ₂ S0 ₄ )

no 152 trichloro

acetic acid 13

3
2
3

3.5
2

2
2.5
until yi

55 52 53

53 53

61 55 82

7 2 anhydrous

72 anhydrous MgSO ₄

15 Cu powder u 83 MgS0 _u water ^H free

■ ar '■

ίο-

(2) Isoamyl nitrite method.

Solutions of 375 ml (325 g, 2.8 mol) of isoamyl nitrite and 378 g (2.0 mol) of crude 4-bromo-2-fluoro-aniline in 250 ml of benzene are separated but at the same time dropwise over about 20 hours to 3,500 ml of benzene under hettigem Stir in a nitrogen atmosphere is added and hold in a water bath at 65 ° C. The mixture is over at 65 ° C Left overnight, and then cooled, washed twice with 2 50 ml of water and evaporated. The dark oily residue is dissolved in 7 50 ml of methanol and 4 50 ml of concentrated hydrochloric acid and treated with 138 g (2.1 mol) of zinc granules, which is added in small portions over 6 hours. To complete this "reductive product improvement" the solution with 5H g (1.0 mol) of fine iron filings treated for 0.5 hours. The color of the mixture becomes visibly lighter within 1 hour. The solution is with Dilute 1 liter of water and add 1 liter of Skellysolve B (a mixture of isomeric hexanes) and the liquids are decanted from the remaining metal. The aqueous phase is washed twice with 1 liter of Skelllysolve B (one Mixture of isomeric hexanes), and then this is extracted with water, 1 liter of 1 normal sodium hydroxide solution and 1 liter Water extracted. The solution is then passed through anhydrous sodium sulfate and evaporated, whereby one 389 g of 4-bromo-2-fluoro-biphenyl are obtained. This material will distilled in vacuo, giving a fraction of 282 g (56%) of 2-fluoro-4-bromobiphenyl with a boiling point of 137 to 155 ° C at a pressure of 11 mm of mercury, and this product crystallizes on standing.

Variations on the alkyl nitrite procedure for the preparation of 4-bromo-2-fluorobiphenyl of formula IV ₁ are shown in Table II, as are those

130035 ^3/0 ~ 598

TABLE II

example

NH:

Br

mmol

Isoamyl HO acid

nitrite

Temp. Addition- Off Other time loot

mmol

ml mmol

Hours.

% mmol

CO O O

O '

2) a

2 B

50

50

no 76 trichloro 3 bis

vinegar- 18 3/4

acid

no 76 trichloro 3 bis

vinegar- 18 3/4

acid

87

88

15 Cu powder 83 MgSO ₄

anhydrous

15 Cu powder no MgSO ₄

CD

era

N>

■ ta-

3046322

All process steps are carried out under a nitrogen atmosphere or under a CH ₂ = CH ₂ atmosphere in a device for working with exclusion of moisture.

15.6 g (0.083 mol) of 1,2-dibromoethane are added dropwise to 12.2 g (0.50 g atom) of magnesium in 100 ml of anhydrous ether. After the boiling of the reaction mixture under reflux has subsided, a solution of 104.4 g (0.416 mol) of distilled 4-bromo-2-fluorobiphenyl in 300 ml of ether is added dropwise over 2 hours. This mixture is then refluxed for 1 hour to complete the formation of the Grignard reagent. The mixture is then ^{cooled to -20 0} C and saturated with ethylene gas and 1.08 g (8.5 mol) of anhydrous nickel chloride (NiCl-) are added, and the mixture is heated to room temperature under an atmosphere of ethylene gas at a pressure of 3 to Allowed to warm to 4 atmospheres with vigorous shaking or stirring. After V2 to 2 hours at room temperature (the gas-liquid-chromatography no further changes shows more), the excess ethylene is thoroughly removed from the system by alternately evacuated to a vacuum of 10 inches with vigorous shaking or stirring and aerated again and this operation 6 times. The mixture is then cooled to -10 C, and treated with C0 ₂ ~ gas until no more exothermic reaction occurs. The mixture is then warmed to room temperature and acidified with 150 ml of 6N hydrochloric acid. The organic phase is washed twice with 100 ml of water and then with 4 portions of 100 ml of 1 normal potassium

130035/0598

bicarbonate solution extracted. The combined aqueous extracts are washed 4 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, which is passed over anhydrous sodium sulfate, and then concentrated, whereby a crystalline crude product, namely 2- (2-fluoro-4-biphenylyl) propionic acid I ^f (flurbiprofen) in a yield of 50-80%, based on the starting material biphenyl.

The material is several times from four times its weight (in ml) 10- to 25-% ethyl acetate Recrystallized in Skellysolve B (a mixture of isomeric hexanes) or in heptane, adding 5% by weight of activated carbon (for example Pittsburgh Cal-carbon) as a decolorizing agent in the final crystallization, whereby one Flurbiprofen in 34 to 54% yield, based on the biphenyl, with a melting point of 110 to 114 ° C.

In a preferred embodiment, the Mixed catalyst for the above reaction on a scale of 60 mmol prepared by adding 0.83 ml (1.2 mmol) dropwise a 2-5% solution of triethylaluminum in hexane to a suspension of 164 mg (0.60 mmol) of anhydrous nickel bis (acetylacetonate) in 2 ml of anhydrous diethyl ether in a bath at -14 to -3 5 ° C under a nitrogen or ethylene atmosphere inflicts. The mixture is stirred at the same temperature for 2 hours and then the aryl-Grignard solution added at -20 ° as described above. The uptake of ethylene in this experiment is just as fast as in the experiment using 3 mol% nickel chloride which was not treated before the alkylaluminum reduction. The chemical yield of flurbiprofen

- 41 - 130035/0598

-U-

3045522

determined by gas liquidus chromatography, was 82%.

Example 2 : Preparation of 2- (4-isobutylphenyl) propionic acid I "

Manufacture is carried out according to the following

Formula scheme:

HBr

Isobutylbenzene M.G. : 134.2

p-bromoisobutylbenzene M.G. : 213.1

.r & h

Variant ('without catalyst:

Atmosphere under a nitrogen to a solution of 67.1 g (0.50 mol) of isobutylbenzene in 125 ml of liquid sulfur dioxide and at a cooling to -32 C (in a bath at 5 ⁰ -4 C) during 13 minutes 9 5, 9 g (0.60 mol) of liquid bromine were added. The mixture is left at about -33 ° C. for 1 hour and then treated with 25 ml of water and allowed to warm to room temperature, during which time the sulfur dioxide and the hydrogen bromide formed as a by-product evaporate. The organic phase thus obtained is separated off from the small aqueous phase. The aqueous phase is diluted with 75 ml of water and extracted with methylene chloride. The methylene chloride extracts are combined with the original organic phase and washed with 25 ml of 20% sodium hydroxide

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130035/0598

solution and then twice with half-saturated sodium chloride solution. The organic solution is dried over anhydrous calcium chloride and then concentrated in vacuo, whereby 107.5 g of a light yellow colored oil are obtained.

The gas liquidus chromatography analysis of the product showed 1.4% starting material, namely isobutylbenzene, 5.1% o-bromoisobutylbenzene and 94.0% p-bromoisobutylbenzene. This gives a yield (% of theory) of 5% o-bromoisobutylbenzene and 95% p-bromoisobutylbenzene.

Variant b) using iron powder as a catalyst:

This attempt is very similar to the uncatalyzed reaction, except that the reaction takes place at -50 to -60 ° C after the catalysis has been carried out at -7 ° C.

2 ml of bromine become a slurry of

1.39 g (0.025 g-atom, 5 mol%) iron powder in 125 ml liquid Sulfur dioxide, which is kept at -7 ° C, is added. After 0.5 hours at -7 ° C, the mixture is cooled to -66 ° C and the isobutylbenzene (67.1 g, 0.5 mole) is added. The reaction mixture is kept at -52 to -60 C, while adding the remainder of a total of 101.9 g (0.64 moles) of bromine, requiring a period of 6.5 minutes. The mixture is kept at -53 to -57 C for 50 minutes, and then treated with 49 ml of water and you work in essentially in the same way as was described in experiment A) above. The crude yield is 106.7 g, the analysis of which shows a content of 0.16 g of isobutylbenzene, 5.9 g of ortho- and 91.3 g of para-bromoisobutylbenzene. From it a yield of 6% o-bromoisobutylbenzene is calculated

- 43 -

130035/0598

and 93% p-bromoisobutylbenzene.

The main difference between this attempt and the previous one is the speed of the Bromination at low temperatures. The gas liquidus chromatography analysis of the reaction product showed about 5% starting material after about 1 hour of reaction time at -33 ° C in the previous reaction and only 0.3% after 1 hour at -57 ^ C in the present case, which indicates that preformed Iron (III) bromide bromination at low temperatures accelerated.

Variant c) using 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) which is at an efcier temperature of -30 C, is cooled to -72 ° C (some solids are formed) and treated with 1.57 ml (10.0 mmol) for less than 3 seconds Isobutylbenzene. The mixture, which contains substantial amounts of solids, is left at -69 to -72 ° C for 70 minutes stirred, and then the reaction is stopped with 1.2 g (10.9 mmol) of resorcinol. The mixture is then allowed to warm to room temperature (the sulfur dioxide evaporates) and the product extracted with hexane. the Hexane solution is washed with aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and diluted with hexane to a volume of 100 ml in order to carry out a gas chromatographic analysis. Due to the The results are as follows: 16% isobutylbenzene, 4% o-bromoisobutylbenzene and 79% p-bromoisobutylbenzene.

130035/0598

This and the following two experiments are comparative experiments on relative reaction rates to be determined at 70 ° C for 6 5 to 70 minutes. The reactions are stopped by adding resorcinol, which reacts almost instantly with the remaining bromine. A conventional test procedure resulted in no catalyst 22% isobutylbenzene, 2% ortho- and 74% para-bromoisobutylbenzene. The higher conversion factor in the present experiment indicates that antimony trichloride increases the rate of reaction.

Variant d) using bromine chloride as the brominating agent:

Bromine chloride (from Dow Chemical, 1.12 g, 9.7 mmol) is condensed in a tube, by applying a cooling with dry ice, and then is diluted with 20 ml of liquid sulfur dioxide, and the solution thus obtained is ⁰ to -72 C chilled. Isobutylbenzene (1.57 ml, 10.0 mmol) is added, and the mixture thus obtained is stirred at -70 ° C. for 6 5 minutes before being quenched with 1.2 g (10.9 mmol) of resorcinol. Working up and analysis as described above gives 8% isobutylbenzene, 6% ortho- and 83% para-bromoisobutylbenzene. This result indicates that bromination is faster with bromine chloride than with molecular bromine and that the degree of ortho-bromination is somewhat higher.

A similar experiment was carried out, except that the BrCl solution was in liquid Sulfur dioxide in isobutylbenzene is added in liquid So at -70 C, and there are yields of 16% each, 5% and 80%.

130035/0598

Variant e) using N-bromosuccinimide:

To a mixture of 1.7 8 g (10 mmol) of N-bromosuccinimide 1.57 ml (10.0 mmol) of isobutylbenzene are added in 20 ml of liquid sulfur dioxide at -30 ° C. The mixture is stirred at -30 to -80 ° C for 65 minutes and then worked up as described above. The analysis only reveals 2% p-bromoisobutylbenzene and 88% raw material recovered, namely isobutylbenzene, and this indicates that the reaction with NBS is very slow at this temperature.

Variant f) catalyzed using N-bromoacetamide by BrCl:

To a mixture of 1.39 g (10 mmol) of N-bromoacetamide in 19 ml liquid sulfur dioxide at -70 ⁰ C were added 1.57 ml of isobutylbenzene (10.0 mmol). The mixture was treated with a solution of 0.05 ml of BrCl in 1.5 ml of SO ₂ and then stirred at -70 ° C. for 65 minutes, after which time it was worked up as described above. Gas liquidus chromatography analysis showed 62% isobutylbenzene, 1.5% ortho-bromoisobutylbenzene and 35% para-bromoisobutylbenzene. This result shows that N-bromine compounds are effective as brominating agents when an acid catalyst (corresponding to HCl) is added. The low temperature reaction in liquid SO- is catalyzed by iron powder or antimony trichloride, but these are not necessary for effective bromination. Bromine chloride is also an effective catalyst for the brominating agent and it gives up to 90% conversion to the p-bromine isomer.

- i * 6 -

130035/0598

^ lbugrofen):

The production takes place according to the following formula

scheme:

+ Mg

1) + ethylene

'Oil' catalyt.

2) - ethylene

MgBr

'MgBr

COOH

A solution of 1.0 ml of 1,2-dibromoethane in 10 ml
anhydrous tetrahydrofuran (THF) is added dropwise during
Added 5 minutes to a mixture of 1.90 g (78 g atom) of magnesium turnings in 10 ml of tetrahydrofuran. The mix will
heated to reflux temperature for 2 minutes, and then treated by adding dropwise over 50 minutes with a solution of 12.85 g (60 mmol) of p-bromoisobutylbenzene in 20 ml of tetrahydrofuran. The mixture thus obtained is during
Heated to reflux for 15 minutes to complete the reaction. The mixture is then cooled to -20 C, and 240 mg of anhydrous nickel chloride are added, and the mixture is allowed to warm to room temperature while stirring or shaking vigorously and working under an atmosphere of ethylene gas at a pressure of 3 to 4 atmospheres. After 0.5 to 2 hours and at a temperature of up to 30 ° C, the uptake of ethylene disappears, and the mixture is evacuated to a negative pressure of -10 inches of mercury, and it is shaken at this pressure for 20 minutes (bath temperature 4 5 ° C) to completely remove excess ethylene
to remove the solution. The mixture is then brought to -15 ° C

- 47 -

130035/0598

cooled and treated with an excess of carbon dioxide gas. The product is made by acidification, extraction of the acidic product from ether with 1 normal potassium hydroxide solution and subsequent acidification of the latter solution, whereby the crude Ibuprpfen is obtained. Based on gas liquidus chromatography analysis the chemical yield of the crude product is 47%. Pure ibuprofen with a melting point from 73-74 ° C is obtained in 91% yield by recrystallizing the sodium salt from water and then acidified.

The many hydratropic acids which can be prepared by the process of the invention are as therapeutic agents well known. For example, see Wong, Chapter 18, Non-Steroidal Anti-Inflammatory Agents (Non-steroidal Anti-inflammatory Agents, Annual Reports in Medicinal Chemistry, Vol. 10, Utility of Hydratropic Acids, Section IV - Metabolic Diseases and Endocrine Function, Ed: Morland, pages 172-181 (1975)), as well as U.S. Patents No. 3,624,142, No. 3,755,427, No. 3,865,949, No. 3,748,705 and No. 4,052,514. Substituted biphenyl compounds are similar, which according to the inventive coupling process Can be produced, either known as therapeutic agents, or as precursors to therapeutic agents Active ingredients. The starting materials as used in. In accordance with the invention Processes are used, can be prepared by known procedures, are known and / or commercially available.

Example 3: Alternative and preferred work-up of flurbiprofen by distillation.

- 48 -

130035/0598

A toluene extract of the crude acids from hydrolysis and extracting the Grignard carboxylation

51.3 g of flurbiprofen according to gas-liquidus chromatography analysis is evaporated and the residue is distilled in vacuo. The fraction, which between 119 - 1-76 ° C (and predominantly 172 - 176 ° C) boils at a pressure of 0.4 to 0.5 ml, is collected (49.2 g, and the product solidifies) and it is crystallized from a mixture of 2.5 ml of ethyl acetate and 170 ml of heptane (decolorization with 0.5 g of Darco G-60 Activated carbon). The dried product weighs 44.6 g (87% yield based on the available product). the Gas liquidus chromatography analysis shows a purity of

98.4%.

Example 4: Bromination of 2-chloroaniline.

A solution of 286 g (1.0 mol) of dibromantine in 300 ml of dimethylformamide is added dropwise over 3 hours to a solution of 250 g (2.0 mol) of 2-chloroaniline in 235 ml of dimethylformamide, and it is maintained at -30 to - 40 C by using an acetone dry ice bath and working under a nitrogen protective gas atmosphere. The mixture is kept in the refrigerator at 0 ⁰ C overnight and then with respect to the starting material, namely, 2-chloroaniline, analyzed by Gasliquidus chromatography analysis. Since a small amount of 2-chloroaniline (about 2%) has remained, an additional amount of 2.86 g (0.01 mol) of dibromantine in 3 ml of dimethylformamide is added, the addition to the reaction mixture, which is heated to -25 ° C is cooled, takes place within 3 minutes. The reaction mixture is then warmed to 20 C, and diluted to exactly 1000 ml with dimethyl

- 49 -

130035/0598

formamide to a sample for gas liquidus chromatography analysis gain weight. The gas liquidus chromatography analysis indicates that the yield of 4-bromo-2-chloroaniline is 99%. The dimethylformamide solution is in a separatory funnel with a mixture of 96 g (1.2 mol) of 50% sodium hydroxide solution, 1.25 liters of 20% methylene chloride in hexane solution and 500 ml of water are shaken. The aqueous phase will extracted with 200 ml of 20% strength methylene chloride in hexane.

The organic phases are washed successively with 500 ml aliquots of water each time and then with 300 ml of methylene chloride diluted once the product begins to crystallize due to the removal of dimethylformamide. The solution is washed with 500 ml of water and then evaporated in vacuo to give a thick slurry receives. This is diluted with 4 50 ml of heptane and heated to dissolve the crystals and then allowed to cool, and then it is inoculated, whereby a mixture of crystals and oil is obtained (this is due to the fact that that DMF is present). The mixture is then heated again and treated with 250 ml of water and cooled and inoculated. The product nicely crystallizes from the two-phase system. It is mixed with 300 ml of water and with 2 50 ml Hexane, which has a temperature of -20 °, washed and dried overnight at room temperature, whereby 367 g (91%) 4-Bromo-2-chloroaniline with a melting point of 69 to 71 ° C.

Example 5: Preparation of 4-bromo-2-chlorobiphenyl.

To a solution of 304 g (4.41 mol) of sodium nitrite and 244 ml of water in 2.5 liters of benzene, with one under

- 50 -

130035/0598

a nitrogen atmosphere in a water bath at 62 ^° C., a solution of 365 g (1.77 mol) of 4-bromo-2-chloroaniline and 212 ml (3.71 mol) of glacial acetic acid in 212 ml of benzene is added dropwise over 8 hours . The dark mixture is stirred overnight. The lower, aqueous layer is removed and the benzene is evaporated at atmospheric pressure. The residue is mixed with 600 ml of methanol and 81.1 g of iron powder, and then 1.093 liters of concentrated hydrochloric acid are slowly added. The mixture is refluxed for 5.5 hours and then diluted with 1.4 liters of hexane and 1.4 liters of water are added and allowed to cool. The slurry obtained in this way is filtered through cellite and it is rinsed thoroughly with hexane. The hexane phase is washed with water, dried over anhydrous magnesium sulfate, stirred with 40 g of activated charcoal (Pittsburgh), filtered off again and evaporated to a constant weight (35 5 g). The Cellit cake is extracted with acetone and worked up separately.

The crude evaporated acetone extract is with a mixture of 200 ml of methylene chloride, 200 ml of 85% sulfuric acid and stirred up 300 ml of hexane. The organic phase is washed three times with 200 ml of 85% sulfuric acid and each Wash solution is back-extracted with 200 ml portions of hexane. The organic phases were finally washed with water washed and concentrated, giving 28 g of an oil which contained a substantial amount of the product.

This was combined with the above 3,55 g of the crude product and chromatographed on 3 kg of silica gel with hexane. Fractions containing the product were collected, pooled and evaporated to constant weight, resulting in a total yield of 292.9 g (62%)

- 51 -

130035/0598

4-Bromo-2-chlorobiphenyl was obtained in the form of a colorless oil. The gas chromatographic-mass spectrometric analysis confirmed the structure: the mass spectrum showed a typical BrCl (bromine chloride) triad at 266 (M +), 268 (base peak) and 270

Example 6: Preparation of 2- (2-chloro- (l, l) -biphenyl-4-yl) propionic acid.

A solution of 2.1 ml (24 mmol) of 1,2-dibromoethane is added under a nitrogen atmosphere to a suspension of 3.8 g (0.156 g-atom) of magnesium turnings in 50 ml of anhydrous ether. As soon as the reaction subsides, a solution of 3 2.4 g (121 mmol) of 4-bromo-2-chlorobiphenyl in 40 ml of anhydrous ether is slowly added over a period of 2 hours. The reaction mixture is kept near the boiling temperature during the addition and the reaction is completed by continuing to reflux the mixture for 15 minutes after the addition is complete. The mixture is transferred then butt Parr-in, and cooled to lower than -20 ⁰ C, and there are added 470 mg of anhydrous nickel chloride, and the piston is clamped in a Parr shaker and under an atmosphere of ethylene gas at a pressure shaken at 60 psig (pounds per square inch gauge). The mixture is then shaken vigorously without heating for 15 minutes, during which time the temperature of the ingredients rises to 20 ° C. It is cooled with water in a cooling jacket in order to maintain a temperature of 28-30 ° C. After a total of 38 minutes, the uptake of ethylene gas decreases. The excess pressure is released and the mixture is shaken, evacuating from time to time

-52-

130035/0598

maintain sub-atmospheric pressure (1-8 inches vacuum) for about Y2 hours. The mixture is then cooled to approximately -13 ° C by circulating a coolant at a temperature of -35 ° in the cooling jacket. The flask is then filled with dry carbon dioxide gas to a pressure of 20 pounds per square inch gauge and the mixture is shaken for about 0.5 hour during which time the temperature increases to 20 ° C.

The excess pressure is released and the reaction mixture is treated with an excess of 1 normal hydrogen chloride acidified. The ether layer is separated off, washed twice with 25 ml of water and with a sufficient amount Amount of 1 molar potassium hydroxide solution extracted to a pH of to achieve in 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 an excess of 10% sulfuric acid and extracted with 150 ml or 25 ml portions of ether. The two ether extracts are combined and washed with 50 ml of water and through a cotton plug into a dry container convicted.

The ethereal solution is anhydrous with 250 ml

Dilute ether and stir under an ammonia atmosphere for 0.5 hours to precipitate the ammonium salt. After cooling the slurry in ice, the salt is collected with Washed ether and dried in a stream of nitrogen, whereby 26.4 g (79%) of the ammonium salt as granulated, dirty-white solid is obtained.

The ammonium salt is converted from water, which contains a small amount of ammonia. The free acid

- 53 -

130035/0598

is obtained on acidification of the ammonium salt and it is recrystallized from heptane-ethyl acetate, whereby 18.4 g (58%) of “chlorobiprofen” with a melting point of 134-136 ° C. are obtained.

Example 7: Preparation of 4-bromo-2-fluorobiphenyl;

A slurry containing 1.0 g (15 mmol)

Copper powder, 12.5 g (76.5 mmol) of trichloroacetic acid and 125 ml of benzene are stirred at 23-26 ° C. under a nitrogen blanket for 4 1/2 hours. The slurry is cooled to 6 ° C and 10.5 ml (78.5 mmol) of isoamyl nitrite are added. After waiting of 1V2 minutes, a solution containing 9.5 g (50 mmol) of 4-bromo-2-> fluoroaniline in 50 ml of benzene dropwise added during} / 2 hour, the slurry trains, wherein the temperature of the slurry is between 17 ° and C holds. Once the addition is complete, the green slurry is allowed to warm to 25 ° C and stir at 23-25 ° C overnight.

Analysis by gas liquidus chromatography shows a chemical yield of 88.7%.

130035/0598

Claims (3)

PATENT CLAIMS Iy process for the bromination or chlorination of
2-fluoroaniline, characterized in that the reaction is carried out in a solvent which essentially consists of dimethylformamide or dimethylacetamide. 2. The method according to sensing 1, characterized in that that a bromination of 2-fluoroaniline is carried out. 3. The method according to claim 1, characterized in that that a chlorination of 2-fluoroaniline is carried out. ORIGINAL INSPECTED 130035/0598 - 55 -