Process for preparing therapeutic 2-arylpropionic acids and esters, and novel arylmethylmalonate esters

Abstract: 2-(4-Nitrophenyl)-2-methylmalonate esters are prepar­ ed by reacting 4-nitrophenyl halides with methylmalonate esters in the presence of a base. The base is preferably an alkali metal hydroxide or potassium carbonate. The prod­ ucts can be reduced to the corresponding 2-(4-amino­ phenyl)-2-methylmalonate esters. The 3-fluuro-4-nitrophe­ nyl and 4-amino-3-fluorophenyl deriviatives of both types of esters are novel. The aminophenylmalonate esters may be coupled with a benzene compound and decarboxylated to give 2-aryl­ propionic acids such as flurbiprofen. Alternatively, decarb­ oxylation of the 4-nitrophenylmalonate ester may be fol­ lowed by reduction and coupling, again to give 2-aryl­ propionic acids and esters.

Description: PROCESS FOR PREPARING ARYLMETHYLIALONATE ESTERS, NOVEL PRODUCTS THEREOF, AND PROCESSES FOR CONVERTING THE PRODUCTS TO THERAPEUTIC 2-ARYLPROPIONIC ACIDS AND ESTERS This invention relates to processes for prepararylmethylmalonate esters, certain novel arylmethylmalonate esters, and processes for converting these products to therapeutic 2-arylpropionic acids and esters. Flurbiprofen, i.e. 2-(2-fluoro-4-biphenylyl)propionic acid, has anti-inflammatory activity which is about 240 times that of aspirin and analgesic activity which is about 180 times that of aspirin, in standard laboratory tests. Despite this high activity, the toxicity (LD50) of flurbiprofen is only 1.2-2.4 times greater than that of aspirin, in standard laboratory tests. Diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalon- ate and diethyl 2-(2-chloro-4-aminophenyl)-2-methylmalonate are known as intermediates in the preparation of tertiary amino acid derivatives of 2-(3-chloro-4-aminophenyl)-2propionic acid having anti-inflammatory properties. See Carney et al., "A Potent Non-Steroidal Anti-Inflammatory Agent: 2-53-chloro-4-(3-pyrrolinyl)phenylIpropionic acid Experientia 29/8, p 938 (August 15, 1973); and British Patent Specification No. 1,316,312 partially correspondin to Swiss Patent Specifications Nos. 574,921-2, 574,924-6. In this context, particular note should be taken of Example 1 of Swiss Patent Specification No. 574,924 and also of Makosza et al., "Reactions of Organic Anions, Part LVIII. The Problem of Competitive Nucleophilic Substitution of Ortho- and Para-Halogens in 2,4-Dihalo Nitrobenzenes by some Carbanions", Roczniki Chemii Ann. Soc. Chim. Polonorum 50, p. 1850 (1976). U.S. Patent Specifications Nos. 2,755,427 and 3,793,457 disclose a 9-step synthesis of flurbiprofen, starting from 4-bromoacetophenone. Other syntheses are disclosed in, for example, U.S. Patent Specifications Nos. 3,784,705; 3,901,906; 3,959,364 and 3,624,142; Belgian Patent Specification No. 840,354; German Patent Specifications Nos. 2,533,397 and 2,613,812; and Japan Kokai 75.40,540 (1975). In these published methods, a number of intermediates are involved and/or potentially hazardous reactions or intermediates are employed, e.g. the Schiemann reaction for the introduction of fluorine. Makosza et al, supra, discuss the use of aqueous sodium and potassium hydroxide in chloride displacement by 2-phenylalkanenitriles and phenylacetonitriles, but it is noted that there is no suggestion to extend the use of these bases to the similar chloride displacement, by malonate, which is also discussed. In fact, aqueous sodium hydroxide and potassium carbonate would be expected to interfere with the malonate-chloride displacement reaction by hydrolysing the malonate. Surprisingly, it has been found that good results can be obtained for displacements by malonate e.g. by using essentially non-aqueous alkali metal hydroxide or potassium carbonate. This has the advantage of employing easily handled bases. The methods of preparing biaryls described herein are coupling processes which improve the known Gomberg or Gomberg-Bachmann reaction discussed by March in Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, pages 550-551, 1969 (McGraw-Hill, Inc.). However, March noted that "yields are not high (usually under 40t) because of the many side reactions undergone by diazonium salts" which are described as intermediates therein. Cadogan, in J. Chem. Soc., page 4257 (1962), discloses the use of pentyl nitrite as the diazotising agent with increasing yields of the named biaryls. Other more recent references, such as Dutch Published Patent Application No. 6,500,865, 7/26/75; C.A. 64,5005e (1966), and U.S. Patent Specification No. 3,992,459, disclose various coupling reactions based on the Gomberg or Gomberg-Bachmann citations. The present invention provides novel esters of formulae IIIa and IVa, and also the mono- and di-acids thereof: EMI4.1 wherein R' and R" are the same or different and are selected from the group consisting of alkyl of from 1 to 6 carbon atoms, inclusive or together form a cyclic diester. A compound having the formula EMI4.2 wherein R' and R" are as defined above. A process for the preparation of a compound selected from the group consisting of EMI4.3 wherein R2 is selected from the group consisting of hydrogen, halogen, alkoxy of from 1 to 6 carbon atoms, inclusive, alkoxy carbonyl of from 1 to 6 carbons, inclusive, alkyl of from 1 to 6 carbons, inclusive, cycloalkyl of from 4 to 7 carbons, inclusive, phenyl, cyano, and nitro; which comprises reacting a compound having the formula EMI5.1 wherein R' and R" are as defined above with a compound selected from the group consisting of EMI5.2 wherein R2 is as defined above and X is halogen; in the presence of a base selected from the group consisting of alkali metal hydroxide or potassium carbonate in an aprotic polar solvent such that the reaction mixture is essentially free of water. Further, the present invention includes the above process in combination with an additional step in which the nitro group on compound III is reduced as illustrated by the following schematic: EMI5.3 <tb> <SEP> oCOOR' <SEP> COOR' <tb> H3C-CX <SEP> H3C-C <tb> <SEP> COOR" <SEP> CooR1iv <tb> <SEP> R2 <SEP> 2 <tb> <SEP> reducing <tb> <SEP> NO2 <SEP> step <SEP> i <SEP> NH2 <tb> <SEP> III <tb> Preferred compounds III and IV therein are those in which the R2 group is a fluorine in the position ortho to the NO2 group noted above as the novel compounds IIIa and IVa. Another novel process includes the preparation of an intermediate having the formula EMI6.1 wherein R' is as definea above which comprises reacting a compound having the formula EMI6.2 wherein X and X; may be the same or different and are halogen wit-h the proviso that X is not fluorine with the compound having the formula EMI6.3 in the presence of a base to obtain a compound having the formula EMI6.4 and 2) reacting the compound III1 obtained in step 1) with an alkali metal fluoride to obtain compound III'a above. Of course, this process can also be supplemented by the additional step in which the nitro group on compound III'a is reduced to prepare the preferred compounds IV'a having the formula EMI7.1 The above processes require the selective displacement of X. When X is the same as X1 displacement at X occurs preferentially because X is in a position para to the nitro substituent. However, when X is different than X, then in general, the ease of displacement of one halogen in the presence of another makes it necessary to limit X to a halogen more easily displaced than X,. Thus, the ease of displacement for X with respect to X1 in ranked order of least difficult to displace to most difficult to displace is shown by the following schematic: F Cl > Sr > I Similarly, X is limited by the same dependency on its quality of displacement with respect to R2 when R2 is a halogen in the above processes. Finally, the present invention is a total process for the preparation of a compound selected from the group consisting of EMI7.2 wherein R2 is defined as above and R3 and R4 are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, alkyl of from 1 to 6 carbons, inclusive, alkoxy of from 1 to 6 carbons, inclusive, alkoxycarbonyl having alkoxy of from 1 to 6 carbons, inclusive, aryloxycarbonyl, phenyl, cyano, and cyloalkyl of from 4 to 7 carbons, inclusive; and R is selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbons, inclusive, which comprises 1) reacting a compound selected from the group consisting of EMI8.1 with a compound having the formula EMI8.2 in the presence of a base to prepare a compound selected from the groups consisting of EMI8.3 wherein X, R2, R' and R" are as defined above; 2) reducing the nitro group of compound III from step 1 to produce a compound selected from the group consisting of EMI8.4 3) coupling the compound IV of step 2 with a compound having the formula EMI9.1 to produce a compound selected from the group consisting of EMI9.2 and 4) treating the product VI of step 3 to obtain the compound selected from the group consisting of I above. In this total 4 step process, step 4 consists of decarboxylating and hydrolyzing to obtain either the ester Ia or acid Ib of compound I. Alternative methods to make either the ester Ia or the acid Ib of compound I which differ from the above 4 step process by variations in the combination of steps disclosed above are also understood to be within the present invention and, for example, may be shown schematically as follows: EMI10.1 <tb> <SEP> X <SEP> H3Cs <SEP> / <SEP> COOR' <tb> <SEP> A <SEP> H3C <SEP> \ <SEP> / <SEP> COOR <SEP> . <SEP> IXCOOR" <tb> <SEP> jAR2 <SEP> H3C <SEP> COOR" <SEP> displacing <SEP> i <SEP> e <SEP> R2 <SEP> --+ <tb> <SEP> ) <SEP> ICO <tb> <SEP> iiO? <tb> <SEP> II <tb> <SEP> NO2 <SEP> H <SEP> H <SEP> N02 <SEP> III <tb> decarboxy2 <SEP> H3C-C-COOR' <tb> k3C <SEP> reducing <SEP> H3C-C-COOR' <tb> step) <SEP> step <SEP> R2 <tb> R2 <tb> <SEP> NO2 <SEP> III' <SEP> H2 <SEP> IV' <tb> <SEP> H <tb> <SEP> H3C-C-COOR' <tb> <SEP> coupling <SEP> R2 <SEP> hydrolyzing <tb> <SEP> 3 <tb> <SEP> R4 <SEP> step <tb> <SEP> H <SEP> - <SEP> R3 <tb> <SEP> I <SEP> Ia <tb> <SEP> H3C-C-COOH <SEP> R4 <tb> <SEP> W <SEP> R2 <tb> <SEP> R3 <tb> <SEP> Ib <tb> Preferred compounds I, i.e. both Ia and Ib, are those in which R2 is fluorine on the position adjacent the biaryl linkage and R3 and R4 are both hydrogen. Another variation in the combination of steps disclosed above which is to be understood to be within the present invention, including preferred compounds Ia or Ib, may also be shown by the following schematic: EMI11.1 <tb> <SEP> X <SEP> HCX <SEP> oCOOR <tb> <SEP> XL\COOR' <tb> <SEP> µ <SEP> CH <SEP> vCOOR <SEP> ' <SEP> Js <tb> <SEP> eX, <SEP> * <SEP> CHHN <SEP> CCOR; <SEP> d1sDlacinx <tb> <SEP> NO: <SEP> II, <SEP> / <SEP> COOR <SEP> lylitizi <tb> <SEP> Alkali <SEP> metal <SEP> fluoride/ <tb> H,Cx <SEP> IHoCWR <SEP> COOR' <SEP> coupling <SEP> step <tb> <SEP> COOR' <tb> <SEP> 'aduc- <SEP> /2 <tb> <SEP> na <SEP> \ <SEP> fF-- <SEP> '¸:: <tb> <SEP> NO <SEP> NXI <tb> <SEP> H <tb> <SEP> H > C-C-COOR <SEP> ' <tb> <SEP> H3C-C-COOH <tb> <SEP> Hydrolysis <SEP> 0 <tb> <SEP> "Step <tb> <SEP> F <tb> <SEP> R3 <SEP> ta(F) <tb> <SEP> R <tb> <SEP> 4 <tb> <SEP> Ib <tb> The term "base" above includes the teachings of the prior art to sodium hydride or the teachings of the present invention to sodium or potassium hydroxide and potassium carbonate. The term "halogen" used herein denotes fluoro, chloro, bromo and iodo radicals. Suitable alkyl radicals of from 1 to 6 carbons include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, nhexyl, and isomers thereof and together form.a cyclic diester, similar to 2,2-dialkyl-1,3-dioxane-4,6-dione. An alkoxy is one of the above mentioned alkyl radicals attached to an oxygen to form corresponding oxy radicals such as methoxy, ethoxy, etc. Suitable cycloalkyls include, for example, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals. Aryls as used in the term "aryloxycarbonyl" is e.q. phenyl or phenyl substituted with, for example, one or more halogen atoms. In the present invention process, the intermediates generated and the reactions used offer a low-hazard potential compared to previously described processes. Also, the reactions can be carried out without purification of the intermediates. Thus, the invention provides a particularly efficient and economic process. EMI12.1 The reaction of a substituted or unsubstituted 4-halonitrobenzene II with a dialkyl ester of 2methylmalonic acid is carried out in the presence of a base, preferably an essentially non-aqueous base, such as alkali hydroxide e.g., sodium or poassium hydroxide or potassium carbonates; and with solid sodium hydroxide especially preferred. The sodium hydroxide in solid form comprises pellets, flakes or powder. The reaction is carried out in aprotic polar solvents, such as dimethylformamide and dimethylsulfoxide at a temperature of O" C to 100" C. Temperatures of from 25 C to 35" C and reaction times of 2 to 5 hours are preferred when using sodium hydroxide as the base. More rigorous reaction conditions, i.e., long reaction times or elevated temperatures are required when using potassium carbonate as the base. The reactants give high yields of compounds III when used in equimolar quantities and in concentration of about 0.75-0.88 molar solutions, however, other concentrations can be used. Generally, a very slight excess of both base and diethyl methylmalonate is preferred. The use of strictly anhydrous conditions or a preformed enolate is unnecessary in the above displacement reaction. However, the use of solvents such as methylene chloride and toluene in phase transfer conditions, taught for similar displacements by 2-phenylalkanenitriles and phenylacetonitriles of the prior art, are not effective for reactions carried out in the presence of sodium or potassium hydroxide and potassium carbonate bases. Isolation of the compound III is accomplished by dilution of the reaction mixture with water and extraction therefrom of the compound III with an organic solvent, e.g. ethyl acetate. Further, purification is unnecessary for the reduction step of the invention process to obtain the preferred fluoro substituted intermediate IIIb noted above. The reduction of the nitro group in compound III is accomplished by known methods such as catalytically with hydrogen and a noble metal catalyst or chemically using any one of a variety of well-known reducing agents, such as iron or tin in an aqueous acidic medium, with sodium dithionite or with zinc in acetic acid. The catalytic reduction with hydrogen may be carried out by standard methods, e.g., in a Parr apparatus with compound III in solution. A variety of solvents can be used, such as lower alkanols, aliphatic hydrocarbons having a boiling point over 350 C, chlorocarbons, ethyl acetate and the like, or aromatic liquid hydrocarbons. A variety of standard noble metal hydrogenation catalysts can be used; palladium or platinum on carbon is preferred. Hydrogen pressures of from 1 up to several atmospheres can be used. Filtration rempves the catalyst and the resulting compound IV in solution may be used without further purification in the coupling step. Chemical reduction can also be carried out, for example, with powdered iron in a water-ethanol mixture in the presence of ammonium chloride. High conversion can be achieved at temperatures of about 50-800C. Best results for obtaining compound IV are obtained by catalytic hydrogenation. Since the compound IV amine is sensitive to air in both the above reductions, an inert, e.g. nitrogen, atmosphere should be used. Although the known-Gomberg-Bachmann reaction described above may be used as the coupling reaction in the total process of this invention, the use of improved coupling reactions as discussed in detail in our copending British Patent Application also filed on Zth December 1980 (Agents Ref: GJE 6180/199), based on USSN 105,062, is desirable. They are generally described as follows: First, in the preferred embodiment of the coupling reaction, a benzene solution of compound IV is added simultaneously with an acid to a non-aqueous mixture of excess compound V and solid sodium or potassium nitrite. Alternatively, a benzene solution of compound IV is added simultaneously with an acid to a mixture of excess compound V and an aqueous solution of sodium or potassium nitrite. The ratio of the amount of compounds IV to V is preferably from 5:10 to 1:10. The acid may be mineral acid such as sulfuric acid or an organic acid such as benzoic, chloroacetic, dichloroacetic, trichloroacetic, methanesulfonic or acetic acid. The temperature of the reaction mixture is maintained between 25 0C and the boiling temperature of the mixture. Molar ratios of acid and sodium or potassium nitrite to compound IV are preferably each from 1:1 to 4:1 times, most preferably 2.5:1. In an especially preferred embodiment, the compound IV and acetic acid are added dropwise to a mixture of the aqueous or nonaqueous metal nitrite in the compound V. Stirring from 2 to 18 hours after the addition is completed at the preferred temperatures of the reaction is advantageous. The product VI is isolated by cooling the reaction mixture washing, evaporating, distilling, or other conventional procedures. A particularly simple and preferred work up is evaporation, dissolution in 85% aqueous sulfuric acid and extraction of the product into hexane. Crude product VI is obtained and further purification may not be necessary for use of the product in making compounds I or Ia. On the other hand, nitro compounds may be by-products in this reaction, so it may be advantageous to reduce the reaction mixture by adding iron/hydrochloric acid, zinc/acetic acid mixtures or sodium dithionite, which converts these byproducts to amines, such that these can be removed from the product simply by washing with acid. Conditions for the reduction of nitro compounds are similar to those outlined by S. R. Faudler et al., in "Organic Functional Group Preparation", Vol. 1, Academic Press, New York, 1968, p. 339. If the coupling reaction is carried out in nonaqueous conditions with solid metal nitrite, it is also advantageous to add an absorbent for water, such as anhydrous magnesium sulfate, silica gel or Elite R. Furthermore, the use of potassium nitrite rather than sodium nitrite in this reaction gives a higher yield and is therefore among the preferred conditions for the anhydrous coupling reaction. In addition to the above named acids for use in this reaction it is found that in the two phase aqueous reaction mixture hydrofluoric and fluoboric are effective. However, fluoboric acid (HBF4) gives a particularly high and unexpected yield. If sulfuric acid is used a 10% solution is preferred. In preparing the especially preferred diethyl 2 (2-fluoro-4-biphenylyl)-2-methyl malonate compound VI for use in subsequent reactions according to the novel methods described herein the temperature of the coupling reaction is 25' to 80 C. and preferably 68 -70 C.- The alternative coupling reaction, also noted above, employs alkyl nitrites instead of sodium nitrite and is accomplished in the absence of water. In this reaction a solution of the compound IV in excess benzene is reacted with alkyl nitrite such as isoamyl nitrite in the presence of the compound V at 20 to 80" C over a period of 5 to 20 hours. Preferably in this embodiment of the invention, isoamyl nitrite and a solution of the compound IV in benzene are each added dropwise separately but simultaneously over a period of about 20 hours to an excess amount of the compound V while maintaining the temperature in the range of 25 C to the boiling point of the solvent, preferably about 650 C. The product VI may be treated with a reducing agent and isolated in a manner analogous to that described above for the preferred coupling reaction using metal nitrite. It is also understood that the above coupling reaction is not limited to the novel process conditions of the copending application described herein. For example, conditions similar to those described in U.S. Patent 3,992,459 may be used to react compounds V and IV above. These conditions include the use of copper or copper salt. Of particular interest is.Example 5 wherein diethyl 2-(4-amino-3-fluorophenyl )-2-methyl malonate is substituted for the corresponding reactant, 2,4difluoroaniline. However, some disadvantages exist in the recovery of the copper and/or disposal thereof which may distinguish the coupling reaction preparing VI of this invention noted above from U.S. Patent 3,992,459. On the other hand, each of the noted coupling reactions disclosed herein may be further modified by conducting the reaction in the presence of copper. Especially preferred is the use of the nonaqueous medium with solid sodium or potassium nitrite described herein with copper. This copper may be in the form of a copper powder or a copper salt. However, if a copper powder is chosen reaction condi tions are used which assure a timely preparation of copper salt in situ. The step 4 treatment of compound VI which converts it to the acid Ib can be carried out by any known decarboxylation and hydrolysis. For example, compound VI may be reacted with an alkali hydroxide to obtain a dialkali salt thereof, acidified to obtain a malonic acid, and heated to achieve decarboxylation resulting in the desired acid Ib. The first part of this process is preferably carried out in a nitrogen atmosphere with an alkali hydroxide in aqueous alkanol at 0-25 C. The alkali hydroxide can be lithium, sodium, or potassium with sodium preferred. Al kanol s such as methanol, ethanol, l-propanol, 2-propanol can be used with aqueous ethanol preferred. The ratio of the alkali hydroxide to the diester VI is between 2.5 and 6 moles per mole of diester. After the saponification is complete, the reaction mixture is diluted and acidified with a mineral acid such as hydrochloric acid, dilute sulfuric acid, or an organic acid such as acetic acid. The thus produced free malonic acid is extracted with an organic solvent, e.g., ethyl acetate, methylene dichloride, and the like. The extracted material is evaporated and the residue dissolved in glacial acetic acid and heated to reflux for 1 to 10 hours to effect decarboxylation. The resulting product is compound Ib, which is isolated and purified by conventional methods, e.g., evaporation, extraction, crystallization and the like. The hydrolysis of the ester and decarboxylation of the diacid can also be carried out simultaneously by refluxing the malonate VI with acetic acid and a strong mineral acid. A good mixture for this is about 2-3 volume parts of acetic acid with 1 part of 4N-8N aqueous hydrochloric acid. The reaction time for the refluxing process is about 18-48 hours, for which reason the earlier base hydrolysis is preferred. On the other hand treatment of the compound VI which converts it to the ester Ia or acid Ib can also be carried out by methods known to convert malonates directly to the desired monoesters, Ia or further hydrolyzing Ia if desired to Ib. A description of a similar conversion reaction may be found in J. Med. Chem. 10, 1078 (1967); Tetrahedron Letters 215 (1967) or Tetrahedron Letters 957 (1973). The highest yields and most amenable conditions preferred for use here are found in the latter of the above references in which compound VI is heated to temperatures of from 50 C to 200 C preferably 1400 C to 180 C in a salt-solvent system of sodium chloride in wet dimethyl sulfoxide. Carbon dioxide and alkanols are produced in the reaction. Approximately 2 moles of water per mole of compound VI are added to the dimethyl sulfoxide to make it wet and a slight excess of sodium chloride is used. Isolation of the desired compound Ia or Ib above is by conventional methods chosen for advantages dependent on the properties of the product. In the alternative method of the total process of the present invention wherein the decarboxylation step follows the displacement step as shown by the schematic above, procedures similar to those taught by the cited references or generally described herein are used. The reaction step disclosed above and as shown by the following schematic EMI18.1 EMI18.2 <tb> alkali <tb> fluoride <tb> EMI18.3 may generally be accomplished by procedures similar to those described in United States Patent 3,240,824, British Patent 1,469,ion and 1;514,082. Decarboxylation occurs in this process. It is understood that in the total 4 step process disclosed herein for the preparation of the biaryl substituted 2-propionic ester Ia or acid Ib, the individual steps may be accomplished by generally known reaction conditions. However, by utilizing the novel steps noted for various steps in combinations as set forth by the basic 4 step process optimum advantages accrue to the disclosure of these combinations. For example, sodium hydride in a polar solvent under reaction conditions of prior art reference may be used to accomplish the displacing step for disclosed compounds also found herein. However, these reactants and the conditions required by their use cause the displacement reaction to be less economical, more hazardous and more inconvenient than the conditions now found to be useful in the present invention. Furthermore, the Gomberg and Gomberg-Bachman reactions described in the literature may be used in the coupling step but the novel improvements recited herein and now claimed in the noted co-pending application make this step less hazardous and more economical herein. The following examples illustrate the process of this invention but are not to be construed as limiting. Starting materials for preparing dialkyl 2-(3 fluoro-4-nitrophenyl)-2-methylmalonate and dialkyl 2-(3 fluoro-4-aminophenyl)-2-methylmalonate and for use in the processes of this invention are available or can be prepared by methods described in the prior art. Example 1 Diethyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate III. EMI20.1 A mixture of 50.0 g (0.31 mol) of 2,4-difluoronitrobenzene II, 56.1 g (0.32 mol) ofdiethyl,methylmalonate and 400 ml of dimethylformamide are vigorously stirred. To the stirring mixture is added 13.1 g (0.33 mol) sodium hydroxide in one portion at 25 C, cooling with ice to keep the temperature of the reaction mixture at 25 -30 C during the first hour. Thereafter, stirring is maintained for 3.5 hours, then 800 ml of water is added, the organic layers removed, and the aqueous layer extracted with three 180 ml portions of ethyl acetate-water. The combined organic layer and extracts are washed with diluted sodium sulfate (3 times; a total of 2 liters) and then with 100 ml of saturated sodium sulfate. The solution is then dried over anhydrous sodium sulfate and concentrated in vacuo to give 114.0 g of diethyl 2-(3-fl uoro-4-nitrophenyl )-2-methylmalonate III as an oil which is used as such in the next step. In like runs, the diethyl 2- (3-fl uoro-4-nitro- phenyl)-2-methylmalonate III is purified to give a light yellow oil of boiling range 149"-1510 C at about .02 mm Hg. Examples 2 to 33 Other runs are carried out in a similar manner to Example 1. Table I, below, gives the reactants. The solvent was always dimethylformamide (lOOc aqueous DMF in Example 21). The reactant equivalents are based on one equivalent of 2,4-difluoronitrobenzene (DFNB). DEMI is diethyl 2-methyl malonate. The K2C03 was anhydrous. Table I Example DFNB DEMM Base Base (Molar Conc) (eq.) (eq.) 2 0.75 1.02 Flaked NaOH 1.03 3 0.75 1.02 Flaked NaOH 1.03 4 0.75 1.02 Flaked NaOH 1.03 5 0.75 1.02 Powdered NaOH 1.03 6 0.75 1.02 Flaked NaOH 1.03 7 0.75 1.02 Flaked NaOH 1.2 8 0.75 1.02 Flaked NaOH 1.2 9 0.75 1.2 Flaked NaOH 1.03 10 0.75 1.13 Flaked NaOH 1.2 11 0.88 1.02 Flaked NaOH 1.03 12 0.88 1.02 Flaked NaOH 1.2 13 0.88 1.02 Flaked NaOH 1.3 14 0.88 1.02 Flaked NaOH 1.2 15 1.26 1.02 Flaked NaOH 1.2 16 3.14 1.02 Flaked NaOH 1.2 17 0.38 2.0 Flaked NaOH 2.07 18 0.75 1.0 K2C03 (60 mesh) 1.0 19 0.75 1.02 K2C03 (60 mesh) 1.15 20 0.75 1.02 K2C03 (60 mesh) 1.1 21 0.75 1.02 K2C03 (60 mesh) 1.1 22 0.75 1.02 K2C03 (60 mesh) 1.25 23 0.38 1.02 K2C03 (300 mesh) 1.25 24 0.75 1.28 K2C03 (60 mesh) 1.25 25 0.75 1.02 K2C03 (300 mesh) 1.25 26 0.75 1.02 K2C03 (60 mesh) 1.25 27 0.75 1.02 K2C03 (60 mesh) 1.5 28 0.75 1.02 K2C03 (60 mesh) 1.25 29 0.75 1.02 K2C03 (60 mesh) 1.25 30 0.75 1.02 K2C03 (300 mesh) 1.25 31 0.75 1.02 K2C03 (300 mesh) 1.25 32 0.75 1.02 K2C03 (300 mesh) 1.25 33 0.75 1.02 Na2C03 1.25 Table II below, gives the conditions and results. A temperature given as 25 means that was the initial temperature, the exotherm being uncontrolled; < 30 means an initial temperature of 5-15 0C with control maintaining the temperature below 300C; 25-30 means an initial temperature of 25 0C with control maintaining the temperature between 25 and 300 C throughout the reaction. The yields were determined by gas-liquid chromatography. Further results were obtained by continuing the process of Examples 2,4,5,14,22,24 and 25 to, respectively, 20,20,20,20,50,53 and 43 hours. The respective initially read yields, as given in Table II, of 79,84,84,74,60,51 and 73t had changed to 77,79,75, 81,73 and 75t. Table II Example Temperature Time Yield (oC) (Hours) (%) 2 C30 5 79 3 24-30 6 88 4 25 6 84 5 25 6 84 6 50 6 72 7 25 3 87 8 < 30 3 80 9 25 6 81 10 25 2 73 11 25-30 6 87 12 < 30 16 89 13 < 30 16 74 14 25 1 74 15 25 1 63 16 25 1 54 17 25 20 60 18 25 20 19 60 18 58 20 60 19 65 21 60 18 37 22 60 23 60 23 60 21 78 24 60 23 51 25 60 18 73 26 60 28 69 27 60 25 58 28 90 23 61 29 120 20 77 30 120 16 86 31 140 2.5 73 32 155 1 79 33 60 44 11 The examples confirm that yields above 85X can be obtained. Though dimethylformamide is the preferred solvent, other aprotic polar solvents such as other amides, dimethylsulfoxide, sulfolane, hexamethyl phosphoric triamide, and others, can be used. Using conditions similar to Examples 1-33, the following compounds III can be prepared: dimethyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, di-n-propyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, diisopropyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, di-n-butyl 2-(3-fluoro-4-nitrophenyl )-2-methyl- malonate, diisobutyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, disecondarybutyl 2-(3-fluoro-4-nitro-phenyl)-2- methylmalonate, ditertiarybutyl 2-(3-fluoro-4-nitro-phenyl)-2 methylmalonate, di-n-pentyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, diisopentyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, dineopentyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, di-n-hexyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, diisohexyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, dineohexyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, methyl ethyl 2-(3-fluoro-4.nitrophenyl )-2-methyl- malonate, propyl butyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, pentyl hexyl 2-(3-fluoro-4-nitrophenyl)-2-methyl malonate, Example 34 Alternate method to intermediate for directly making monoesters Ia: Ethyl.2-(3-fl uoro-4-nitrophenyl )propionate. EMI25.1 A mixture of 100 millimoles of diethyl 2-(3fluoro-4-nitrophenyl)-2-methylmalonate, 110 millimoles of sodium chloride and 50 milliliters of dimethyl sulfoxide is heated under nitrogen at about 1300 to 1800 C for about 6 hours. On cooling the mixture is diluted with 100 milliliters of water and 100 milliliters of ethyl acetate. The layers are separated and the organic layer is washed two times with 25 milliliters of water. After drying over sodium sulfate the organic layer is concentrated in vacuo to give the desired ethyl 2-(3-fluoro-4-nitro phenyl )propionate. Example 35 Diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate IV. EMI25.2 To a solution of 41.6 g diethyl 2-(4-nitro-3 fluorophenyl)-2-methylmalonate III in 210 ml ethyl acetate in a 500-ml Parr hydrogenation bottle is added 830 mg (2 wt %) of 5% palladium/carbon. The mixture is hydrogenated in a Parr apparatus at 25wC under 10-12 psi hydrogen for 2.5 hours. The catalyst is removed by filtration through diatomaceous earth (Celite EMI26.1 and is washed with a few ml of ethyl acetate . The solvent is removed in vacuo to give diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate as a viscous oil, 37.6 g 100 , wt. yields. This material is used without purification. Chemical reduction of compound IIIa. To a solution of 9.86 g (31.51 mmol) diethyl 2 (4-nitro-3-fluorophenyl)-2-methylmalonate in 60 ml of 50% aqueous ethanol is added 10.0 g (18tri.92 mmol) of solid ammonium chloride followed by a 4.48 g (80.21 mmol, 2.55 equiv.) of 40 mesh activated iron filings. The resulting mixture is stirred under nitrogen in an oil bath at 60 C for 4.5 hours and let stand at room temperature for 12 hours. The reaction mixture is filtered through diatomaceous earth (Celite EMI26.2 and the solids are washed several times with 50% aqueous ethanol. The combined filtrates are concentrated in vacuo to remove most of the ethanol and are then diluted with 100 ml water. Extraction with 2 x 50 ml ethyl acetate gives an organic fraction which is washed with dilute aqueous sodium sulfate and dried over sodium sulfate. Concentration in vacuo gives 8.44 g (94.6% yield) diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate (IVa) as a dark brown oil which gives- by distillation an almost colorless oil of boiling point of about 190 C at 0.1 mm Hg. Since the amine in both reactions above is air sensitive (darkens on exposure), all manipulations can be carried out under nitrogen. EMI26.3 <tb> SaTilqj <SEP> tu <SEP> Cxample-35 <SEP> the <SEP> chemical <SEP> reducti > <tb> <SEP> repeated <SEP> as <SEP> shown <SEP> in <SEP> Examples <SEP> 36 <SEP> the <SEP> fol <tb> <SEP> lowing <SEP> conditi <SEP> 1 <SEP> h <SEP> the <SEP> following <SEP> results <SEP> (Table <tb> Examples 36 to 41 The procedure of Example 35 was repeated under various conditions, still using 50% aqueous ethanol as the solvent and a reaction temperature of 6OOC, except that 25 0C was used in Example 40. The reactants and results are given in Table III. Table III Example Reactant Iron Time Yield (Form) (Hours) (t) 36 12N HCl 40 mesh 6 80 37 12N HC1 (20 mol %) 40 mesh 4 80 38 12N HC1 (10 mol %) Powder 4 80 39 6eq. NH4C1 40 mesh 5 95 40 6eq. NH4C1 40 mesh 20 95 41 6eq. NH4C1 Powder 5 95 The 40 mesh iron filings are used in an activated form, achieved by treating 10 g of the iron filings with 2 ml 12N aqueous HC1, followed by drying under nitrogen. See Jenkins et al, IND. Chem. Eng. 22 (1930) 31. Using conditions similar to Example 34, the following compounds IV can be prepared: dimethyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, di-n-propyl 2- (3-fl uoro-4-aminophenyl )-2-methyl - malonate, diisopropyl 2-(3-fluoro-4-aminophenyl)-2-methyl- malonate, di-n-butyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, diisobutyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, disecondarybutyl 2-(3-fluoro-4-aminophenyl)-2 methylmalonate, ditertiarybutyl 2-(3-fluoro-4-aminophenyl)-2 methylmalonate, di-n-pentyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, diisopentyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, dineopentyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, di-n-hexyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, diisohexyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, dineohexyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, methyl ethyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, propyl butyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, pentyl hexyl 2-(3-fluoro-4-aminophenyl)-2-methyl malonate, dimethyl 2-(3-fluoro-4-aminophenyl)-2-methyl- malonate, Example 42 Diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI with the nitrite and acid procedure. EMI29.1 In a one-liter round bottom flask is placed 18.34 g (0.266 mol., 2 equiv.) of sodium nitrite, 22 ml of water, and 210 ml of benzene V. The mixture is placed in an oil bath at N68-70" C and is stirred vigorously. A solution of 37.6 g of diethyl 2-(4-amino-3-fluorophenyl)-2methylmalonate IV, 16.0 g (0.266 mol, 2 equiv.) of glacial acetic acid, and 70 ml of benzene are added from an addition funnel dropwise overlY6 hours. Heating is continued for 2 hours after addition is complete, and the mixture is then allowed to stand overnight. The resultting mixture is transferred to a one-liter separatory funnel and the benzene layer is washed with 3 x 100 ml of dilute aqueous sodium sulfate solution. Concentration in vacuo gives a dark brown viscous oil, 47.8 g. The crude product VI is dissolved in 66.5 ml of aq. sulfuric acid (855 v/v) and the resulting solution is extracted with 4 x 500 ml hexane. The combined hexane extracts are washed with 4 x 500 ml 1M aqueous sodium carbonate solution and 100 ml of saturated aqueous sodium sulfate. Removal of the solvent in vacuo gives 26.5 g of diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI as a light yellow viscous oil (58% yield overall from difluoronitrobenzene II). In a manner similar to Example 42, diethyl 2-2 -fluoro-4-biphenylyl)-2-methylmalonate VI under slightly varying conditions is obtained in yields varying from 53-61 . Example 43 Diethyl 2-(2-fl uoro-4-biphenylyl )-2-methylmaionate VI with the alkyl nitrite procedure EMI30.1 EMI30.2 <tb> alkyl <SEP> \ <tb> nitrité <tb> EMI30.3 In a one-liter round-bottom flask is placed 250 ml of benzene V. A solution of ¯ 9.1 9 (from 31.44 mmol) of diethyl 2-(3-fluoro-4-aminophenyl ).2-methylmalonate IV in 110 ml benzene is placed in one funnel and a solution of 10.1 g (86.5 mmol, 2.75 equiv.) isoamyl nitrite in 50 ml benzene is placed in the other. With vigorous stirring at /v 58" C, 0.35 g (3.0 mmol) of isoamyl nitrite is added to the reaction flask. The solutions of amine and nitrite are added simultaneously over 7 hours. When addition is complete, stirring is continued for 4 hours at 59 C and the mixture is then allowed to stand for 12 hours. The solvent is removed in vacuo and the resulting dark brown oil (12.0 g) is transferred to a 250 ml separatory funnel. Ice cold 85% (v/v) aqueous sulfuric acid (16 ml) is added and the mixture is extracted with 4 x 120 ml hexane. The combined hexane extracts are washed with 4 x 100 ml of 1M aqueous sodium carbonate, 50 ml of saturated aqueous sodium sulfate solution, and are dried over anhydrous sodium sulfate. Concentration in vacuo gives 6.32 g of 2-(2-fluoro-4-biphenylyl )-2-methylmalonate VI as a yellow oil (58.0% based on 2,4-difluoronitrobenzene II). In a manner similar to Example 43, diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate is obtained under varying conditions in a yield of 52-72 . Example 44 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen)Ib. EMI31.1 Method A To a stirred solution of 7.58 g (22.0 mmol) of diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI in 50 ml of absolute ethanol, maintained under nitrogen gas at N15" C (ice bath) is added 8.72 g (109.0 mmol, 5.0 mol -equiv.) of 50% aqueous sodium hydroxide. The temperature is maintained at < 250 C for 6 hours. The resulting suspension is diluted with 150 ml water and the pH is adjusted to8.0 with dilute hydrochloric acid. The solution is transferred to a separatory funnel and is extracted with 3 x 60 ml of methylene chloride. The aqueous layer is acidified to pH < 1 with concentrated hydrochloric acid and is then extracted with 200 ml of ethyl acetate in three portions. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.9 g 2-(2-fluoro-4-biphenylyl)-2-methyl malonic acid. This material is dissolved in 15 ml of glacial acetic acid and the solution is heated to reflux fowl7 hours. Water (15 ml) is added and the solution is allowed to cool slowly with stirring and seeding. After 1 hour stirring at room temperature, the mixture is cooled with stirring to 0-5 C, then let stand for Ni5 hours. The product is' isolated and washed with a few ml of cold 50% aqueous acetic acid then dried to give 4.67 g flurbiprofen Ib of melting point 113 -115 C. Method B In a 200 ml round-bottom flask is placed 15.03 g (43.7 mmol) of ethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalon- ate, 62 ml of glacial acetic acid, and 22 ml of 6N aqueous hydrochloric acid. The mixture is refluxed under nitrogen for 24 hours. On cooling to room temperature, the solution is diluted with 250 ml of water and the mixture is extracted with 4 x 50 ml of methylene chloride. The combined extracts are washed with 2 x 100 ml of water and then with 8 x 40 ml (0.2N) of aqueous potassium hydroxide solution. Extracts 1-4 are-- combined, acidified to pH < 1 with concentrated hydrochloric acid, and the resulting solution is extracted with 3 x 50 ml of methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in vacuo to give 7.13 g (38.8X overall) crude flurbiprofen. Extract 5 is backwashed with 3 x 15 ml methylene chloride, acidified with concentrated hydrochloric acid, and the resulting mixture is extracted with 3 x 20 ml methylene chloride to give 1.84 g (10.0%) crude flurbiprofen. Fractions 6-8 are combined and the pH is adjusted to9.0. After washing with 3 x 30 ml methylene chloride, the aqueous is acidified with concentrated hydrochloric acid and is then extracted with 3 x 50 ml of methylene chloride. Drying and concentration of the extracts gives 0.53 g (4.0X) crude flurbiprofen Ib. The combined crude flurbiprofen Ib (9.5 g) iscrystallized from 59 ml of 50X aqueous acetic acid as previously described to give 8.80 g of flurbiprofen Ib (82.6X conversion from malonate VI; 47.9X overall from 2,4-difluoronitrobenzene II). Method C In a 200 ml round bottom flask is placed 10.0 g (-u 29.1 mmol) of diethyl 2-(2fluoro-4-biphenylyl)-methyl- malonate VI, 9.4 g (167.9 mmol, 6 equiv.) of solid potassium hydroxide, 33 ml of absolute ethanol, and 60 ml water. The resulting two-phase mixture is¯ stirred under reflux for 17 hours. Most of the ethanol is removed in vacuo and the residue is diluted with 100 ml water. The pH is adjusted to ,W8 with hydrochloric acid. The aqueous solution is extracted with 5 x 100 ml methylene chloride. The aqueous layer is acidified with 6N hydrochloric acid to a pH S1 and is then extracted with 50 ml of methylene chloride and 3 x 50 ml of ethyl acetate. The combined organic extracts are washed with dilute aqueous sodium sulfate solution and dried over anhydrous sodium sulfate. Concentration in vacuo gives 6.38 g of tan solids. This material is dissolved in 12 ml of glacial acetic acid and the solution is heated to reflux for 17 hours at which time activated charcoal (Darco G-70) (600 mg) is added. After an additional 3 hours the solution is filtered and the filtrate is diluted with water to give ca. 50% aqueous acetic acid solution. On seeding at 800 C and further cooling, the product crystallizes to give an isolation 5.63 g (45.3% overall yield) of flurbiprofen Ib. Example 45 Ethyl 2-(2-fluoro-4-biphenylyl)propionate. EMI33.1 A mixture of 100 millimoles diethyl 2-(2-fluoro-4biphenylyl)-methylmalonate VI, 110 millimoles sodium chloride, 200 millimoles water and 50 milliliters dimethyl sulfoxide is heated under nitrogen at about 130 to 180 C for about 6 hours. On cooling the mixture is diluted with 100 milliliters water and 100 milliliters ethyl acetate. The layers are separated and the organic layer is washed two times with 25 milliliters of water. After drying over disodium sulfate the organic layer is concentrated in vacuo to give the desired ethyl 2-(2-fluoro-4-biphenyl yl)propionate. The mono- and di-acids of the esters of formulae III and IVa compounds may be prepared from the esters by known methods such as hydrolysis.

Claims: CLAIMS 1. A process for preparing a compound of formula III EMI35.1 wherein R2 is hydrogen, halogen, C16 alkoxy, (C1 6 alkoxy)carbonyl, C1-6 alkyl, C47 cycloalkyl, phenyl, cyano or nitro; and either R' and R" are the same or different C16 alkyl groups or R' and R" together are alkylene, which comprises reacting a compound of formula II EMI35.2 wherein R2 is as defined above and X is halogen, with a methylmalonate ester of the formula EMI35.3 wherein R' and R" are as defined above, in the presence of a base. 2. A process according to claim 1 characterised in that the base is an alkali metal hydroxide or potassium carbonate, preferably sodium hydroxide. 3. A process according to claim 1 or claim 2 characterised in that it is conducted in the presence of an aprotic solventandis gbstntially free of water. 4. A process according to any preceding claim characterised in that it is conducted at from 0 to 1000C, preferably 25 to 35 C. preceding 5. A process according to any/claim characterised in that R2 is at the ortho-position with respect to the nitro group. 6. A piocess according to claim 2 characterised in that R2, is a halogen atom of no greater reactivity than X with respect to the methylmalonate ester and the product has the formula EMI36.1 wherein R' and R" are as defined in claim 1 and X1 is a halogen atom as defined above. 7. A process according to claim 6 characterised in that X1 is less reactive than X. 8. A process according to claim 6 characterised in that the compound of formula II is 2,4-difluoronitrobenzene. 9. A compound of the formula EMI36.2 wherein R' and R" -are as defined in claim 1, or a mono- or di-acid form thereof, preferably diethyl 2-(3-fluorophenyl4-nitro)-2-methylmalonate. 10. A process for preparing a compound of formula IV EMI37.1 wherein R2, R' and R" are as defined in claim 1, which comprises reducing the product of a process according to any of claims 1 to 8 or an ester as claimed in claim 9. 11. A compound of the formula EMI37.2 wherein R' and R" are as defined in claim 1, or a mono- or di-acid form thereof, preferably diethyl 2-(4-amino-3fluorophenyl)-2-methylmalonate. 12. A process for preparing a compound of formula I EMI37.3 wherein R2 is as defined in claim 1; R is hydrogen or C16 alkyl; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen, nitro, C1-6 alkyl, C16 alkoxy, (C1-6alkoxy)carbonyl, aryloxycarbonyl, phenyl, cyano and C47 cycloalkyl, which comprises coupling a compound of formula V EMI38.1 wherein R3 and R4 are as defined above, with the product of a process according to claim 10 or an ester as claimed in claim 11 to produce a compound of formula VI EMI38.2 wherein R2, R3 and R4 are as defined above and k' and R" are as defined in claim 1, and converting the compound of formula VI to the compound of formula I. 13. A process for preparing a compound of formula III' EMI38.3 wherein R2, R' and R" are as defined in claim 1, which comprises decarboxylating the product of a process according to any of claims 1 to 8 or an ester as claimed in claim 9. 14. A process for preparing a compound of the formula EMI39.1 wherein R is C16 alkyl, which comprises reacting the product of a process according to claim 6 with an alkali metal fluoride. 15. A process for preparing a compound of formula IV' EMI39.2 wherein R2 and R' are as defined in claim l, which comprises reducing the product of a process according to claim 13 or claim 14. 16. A process for preparing a compound of formula IVa EMI39.3 wherein R' is as defined in claim 4, which comprises reducing the product of a process according to claim 13 or claim 14. 1". A process for preparing a compound of formula I as defined in claim 7, which comprises coupling the product of a process according to claim 15 or claim 16 with a compound of formula V as defined in claim 12, and, if desired, hydrolysing the acid ester to the acid. 18. A process according to claim 120r claim 17 characterised in that the coupling is conducted in the presence of copper. 19. A process according to any of claims 12, 17 and 18 characterised in that the coupling is conducted in the presence of aqueous metal nitrite and an acid, preferably by adding the compound of formula V and the acid simultaneously to the aqueous sodium nitrite in an excess of the compound of formula V such that the ratio of sodium nitrite to the compound of formula IV is from 1:1 to 4:1 and the ratio of the acid to the compound of formula IV is 1:1 to 4:1. 20. A process according to claim 19 characterised in that the acid is sulfuric, acetic, fluoboric or trichloroacetic acid. 21. A process according to claim 17 or 18 characterised in that the coupling is conducted in the presence of a aqueous metal nitrite and an acid, preferably trichloroacetic acid. 22. A process according to claim 19 or 21 characterised in that the compound of formula V and the acid, preferably acetic acid, are simultaneously added to a mixture of finely divided potassium nitrite in an excess of the compound of formula IV such that the ratio of potassium nitrite to the compound of formula IV is from 1:1 to 4:1 and the ratio of the acid to the compound of formula IV is from 1:1 to 4:1. 23. A process according to any of claims 12, 17 and 18 charaterised in that the coupling is conducted by adding a C38 alkyl nitrite and the compound of formula IV separately and simultaneously to an excess of the compound of formula V. 24. A process according to any of claims 12 and 17 to 23 characterised in that the compound of formula I is 2-(2-fluoro-4-biphenylyl)propionic acid or its ethyl ester.

Inventors: HYLTON, THOMAS ANTHONY, WALKER, JERRY ARNOLD
Applicants: THE UPJOHN COMPANY
Application year: 1980
Main classification: C07C69
IPC codes: C07C51, C07C57, C07C201, C07C229, C07C205, C07C227