NO750465L - - Google Patents

Description

Process for the first 1.1 ing of 5-fluoro-2-methyl-i-(p-methylsulfinylbenzylidene)-indene-3-acetic acid.

The present invention relates to an improved process for the production of 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-inden-3-acetic acid by reacting 2-methyl-6-fluoro-1.-indanone with a lithium compound to form a 2-methyl-5~fluoro-3-indenyl-acetic acid, -ester, -amide, -nitrile or -acid salt, with subsequent condensation of the aforementioned compound with p-methylsulfinyl-(or methylthio)-benzaldehyde, transfer of the side chain to the free acid, and when the methyltbio group is present, oxidation at any stage. Alternatively, 2-methyl-3~[p-methylsulfinyl-(or methylthio )-benzylidene]-6-fluoroindanone can be reacted with the I*ithiumfur compound with subsequent transfer of the side chain to the free acid, and when the methylthio group is present, oxidation .

5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-inden-3-acetic acid is an important anti-inflammatory compound which is described in US patent no. indenylacetic acid by reacting 2-methyl-6-fluoro-1-indanone with an α-haloacetic acid ester under Reformatsky conditions to introduce the aliphatic acid ester side chain. The 1-p-methylsulfinylbenzylidene substituent is then introduced on the inside bond by direct reaction of the indene with p-raethylsulfinyl-benzaldehyde using base as catalyst. The indenester is then hydrolyzed to form the desired compound.

In the Journal of the American Chemical Society for May 2, 1973, page 3050, it is published to use lithium t-butyl acetate for carrying out Reformatsky-type reactions on a carbonyl group, In contrast to the method disclosed in US Patent No. 3,654 -349 the use of a lithium compound would lead to higher overall yields of the desired indenylacetic acid product.

5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid can be prepared in high yield by using 2-methyl-6-fluoro-

1-indanone or 2-methyl-~3~[p-methylsulfinyl-(or methylthio)-benzylidene]-6-fluoro-1-indanone as starting material. Preferably, the process is carried out by first reacting 2-methyl-6-fluoro-1-indanone with the desired lithium compound followed by condensation with p-methylsulfinylbenzaldehyde or p-methylthiobenzaldehyde, transfer to the free acid and oxidation of the methylthio group when p-methylthiobenzaldehyde is used in the condensation . Alternatively, the benzylideneindanone compound is reacted with the lithium compound, followed by transfer of the acid side chain to the free acid, and when necessary, oxidation before or after the transfer to the free acid.

The lithium compound used in the first stage of the reaction has the formula:

where X is COOR, CN or where R is hydrogen, alkyl (preferably C 1 -alkyl), alkali or alkaline earth metal or aralkyl (preferably phenyl-C 1 -alkyl and especially benzyl), and R 1 and R 2 are each alkyl (preferably 1-alkyl), a ryi, aralkyl (preferably phenyl-C 1-4 -alkyl) or substituted alkyl, aryl or aralkyl or R 1 and R 2 can together be cycloalkyl (preferably 1 ); and Y is hydrogen, -P-(OR 1 ) 2 or -Si(R 1 ) 2 , where R 2 is -alkyl, phenyl or benzyl 0 or substituted alkyl, substituted phenyl or substituted benzyl, and especially methyl. Preferably when Y is hydrogen, X is as indicated, and especially COOR and R is C. ~-alkyl, alkali or alkaline earth metal, and especially t-butyl, sodium or lithium; when Y is

is X COOM, and M is hydrogen, alkali or alkaline earth metal and especially lithium; and when Y is -S^R^)^, X is COO-alkyl, especially COOMe and COOEt.

The lithium compounds can be readily prepared as described in the following articles: J.A.C.S., Vol. 89 (1967), pp. 2500-2501;

J. Org. Chem., vol. 36 (1971), page 1151;

J.A.C.S. volume 92, pages 1396-1397;

J.A.C.S., Volume 95, Page 3050;

Tetrahedron Letters No. 9, pages 711-713, (19?//+); and J.A.C.S., Volume 96:5, March 6, 1974.

For the preparation of Li-CI-L, ~X compounds, an example would be as follows: To a suspension of sodium (or potassium or lithium) hydride (or -amide) in tetrahydrofuran is added one equivalent of acetic acid, and the mixture is heated at 40°C. The suspension is then cooled, and one equivalent of butylithium is added at approx. 10°C to form the lithium enolate. The lithium compound suspension can be used "as is" (ie without isolation) in the reaction with the indanone compound. In a similar way, lithio-t-butyl acetate, lithio-methylacetate, litbio-benzyl acetate, lithio-acetonitrile or lithio-dimethylacetamide can be prepared by introducing into a reaction vessel n-butyl lithium dissolved in hexane and diisopropylamine, placing the reaction vessel in a dry ice-acetone bath, adding the appropriate acetic acid compound and stir the reaction mixture for approx. 30 minutes . The product thus formed can be used "as is" (ie without isolation) in the reaction

with the indanone. The compound where Y is

(0R1)2and X is COOH, can

is prepared by treating a substituted or unsubstituted dialkyl or dibenzyl phosphite, and especially dibenzyl phosphite, with methyllithium in tetrahydrofuran, at ~80°C followed by the addition of methyl iodide, which reaction mixture is then treated with methyllithium in tetrahydrofuran at -80°C followed by carbon dioxide for to obtain α-dibenzylphosphono-acetic acid.

The compound where Y is -S^R^)^ and X is COO-alkyl is prepared by treating an alkyl-[tri-(alkyl, phenyl or benzyl)]-silyl acetate (preferably ethyl trimethylsilyl acetate) with lithium dicyclo -hexylamide in dry rahydrofuran at -70°C.

The condensation of the indanone compound with the lithium compound is suitably carried out in the presence of an inert solvent such as Cg aromatic or C^_1^ hydrocarbon solvents (benzene, toluene, hexane, heptane, nonane and the like) or ether (containing up to 10 carbon atoms) such as tetrahydrofuran, diethyl ether , dimethoxyethane and dioxane, as well as the solvents used in the preparation of the enolate compound. Preferably, the reaction is carried out by mixing the reaction mixture of the lithium compound and the indanone in an inert solvent. The reaction can be carried out at temperatures from -80° to 60°C, but preferably from -10° to 40°C until the reaction is substantially complete. Although the molar ratio of lithium compound to indanone is not critical, it is preferred to carry out the reaction with a slight excess of lithium compound, preferably approx. 1.2 to 1. When the reaction is carried out with the Li-CH2-C00R compound, a strong base is added after the initial reaction to complete the dehydration of the hydroxyindene thus formed. For example, bases such as alkali and alkaline earth metal hydroxides (NaOH, KOH) or ^-alkoxides (NaOCH^j K-t-butoxide), tetra-C^g-alkyl-ammonium hydroxide or benzyl-tri-C^^-alkyl-ammonium hydroxides ( benzyltrimethylammonium hydroxide) is used. Preferably, alkyl ammonium hydroxide or benzyl trialkyl ammonium hydroxide is used. The concentration of base is not critical, and consequently can be used from approx. 0.1:1 to 2:1 moles of base to indanone, but preferably from 0.5:1 to 1:1. The dehydration is carried out at a temperature of from 25° to 100°C, and preferably from 50° to 75°C until the reaction is substantially complete.

The introduction of the benzylidene substituent on the indene-acetic acid compound (when the starting material is 6-fluoro-2-methyl-1-indanone) is conveniently carried out by reaction with p-methylsulfinyl-(or methylthio)-benzaldehyde in the presence of a strong base at a temperature from 0° to 100°C, and preferably from 20 to 80°C in the presence of a dissolving agent. The ratio of aldehyde to indene is suitably approx. 1:1 to 2:1, but preferably approx. 1.5:1, and the ratio of base.' to within can vary from a catalytic amount to an equimolar amount or more. Strong bases such as alkali and alkaline earth metal hydroxides or -C-j^-alkoxides such as sodium hydroxide, potassium methoxyd, potassium t-butoxide, tetra-C^^-alkyl ammonium hydroxides or benzyl4ri-C^ --alkyl ammonium hydroxides such as benzyltrimethylammonium hydroxide, can be suitably are used. Suitable solvents are polar solvents such as dimethoxyethane, methanol, pyridine, dimethylformamide and the like, and non-polar solvents such as benzene, toluene, xylene and the like.

The thus produced benzylidene-indene-acetic acid ester, -amide, -nitrile or -acid salt (which is usually transferred to the free acid during work-up) is transferred to the corresponding free acetic acid by ordinary hydrolysis. In the case of the t-butyl ester, pyrolysis can also be used. With the benzyl ester, hydrogenation can also be used. The hydrolysis can be carried out under commonly known acid conditions such as in the presence of strong organic acids (p-toluenesulfonic acid, dinitrobenzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid) or mineral acids (hydrochloric acid, sulfuric acid), and especially hydrochloric acid. Alternatively, the hydrolysis can be carried out under ordinary basic conditions such as by addition of water or aqueous bases followed by acidification to form the free acid.

The oxidation of the methylthio group to the desired methylsulfinyl group can be carried out at any stage in the reaction process, but preferably after the formation of the free acid. The oxidation can be carried out by a number of standard methods such as oxidation with hydrogen peroxide, basic periodates and hypobalogenites (preferably alkali metal or alkaline earth metal periodates and hypohalogenites) or organic peracids such as peracetic acid and monoperphthalic acid, but especially hydrogen peroxide. The reaction is preferably carried out in the presence of a solvent. For such purposes, β-alkanoic acids (acetic acid), halogenated hydrocarbons (chloroform, 1,2-dichloroethane), ethers (dioxane), β-alkanols (isopropanol) or mixtures thereof can be used. The molar ratio of oxidizing agent to indene-acetic acid compound may be from 0.5 to 10, but is preferably from 0.8 to 1.5. The reaction time and temperature are not critical, as the reaction is carried out until it is essentially complete. Preferably, however, the reaction time is from 1 to 18 hours, and in particular 2 to 6 hours, at a temperature of 10 to 80°C, and in particular 25 to 50°C.

The following examples are given to further illustrate the invention.

Example 1

Lithio- nat riumacet at

A suspension of 300 mmol of anhydrous sodium acetate in 500 ml of tetrahydrofuran containing 500 mmol of diisopropylamine is cooled to -20°C, and to this is added 300 mmol of n-butyllithium. After stirring the mixture at room temperature for 2 hours, it contains the lithium sodium acetate suitable for use in the condensation reaction.

Example 2

Dilithioacetate

600 mmol of lithium diisopropylamide are added to 300 mmol of acetic acid in 500 ml of tetrahydrofuran at 0°C. The reaction mixture contains, after stirring at room temperature for 3 hours, dilithioacetate.

Example 3

Lithio - acetone it ril

300 mmol of lithium diisopropylamide are added to 300 mmol of acetonitrile in 500 ml of tetrahydrofuran at 0 - 5°C. After the mixture is allowed to warm to room temperature and is stirred for 3 hours, the reaction mixture contains the lithio-acetonitrile.

In a similar way, when dimethylacetamide or methyl acetate is used instead of acetonitrile in the above example, the lithio-dimethylacetamide or the lithio-acetonitrile is obtained.

Example 4

6- fluoro- 2- methyl- 3-( proethylthiobehzylidene)- indanone

To 0.01 mol of 6-fluoro-2-methylindanone and 0.01 mol of p-methylthiobenzaldehyde, two equivalents of 25% methanolic sodium methoxyd are added. The mixture is refluxed for 2 hours, cooled and neutralized with acetic acid and diluted with water. The reaction mixture is extracted into ethyl acetate, which is washed with water and evaporated, whereby the crude product is obtained.

In a similar way, when p-methylsulfinylbenzaldehyde is used instead of p-methylthiobenzaldehyde in the above example, the p-methylsulfinylbenzylidene compound is obtained.

Example 5

t-butyl-5-fluoro-2-methyl-indenyl-3-acetate

1 mol of 6-fluoro-2-methylindanone is dissolved in 10 volumes of toluene and to this is added 1.1 mol of a molar solution of lithio-1:-butyl acetate in toluene. The reaction mixture is stirred for 1 hour at room temperature, then 0.5 mol of "Triton B" is added, and the mixture is heated for 2 hours at 65°C. The reaction mixture is then washed with water and evaporated, whereby the t-butyl ester of 5-fluoro-2-methyl-indenyl-3-acetic acid is obtained.

In a similar way, when 6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indanone or 6-fluoro-2-methyl-3-(p-methylthiobenzylidene)-indanone is used instead of 6-fluoro-2- the methyl-indanone in the above example, the corresponding t-butyl acetate compound.

Example 6

5- fluoro- 2- methyl- indenyl- 3- acetic acid

To the lithium-sodium acetate reagent from example 1 is added

300 mmol of 6-fluoro-2-methylindanone at 0 - 20°C. The reaction mixture is stirred for 1 hour at room temperature, then 150 mmol of "Triton B" is added, and the mixture is heated at 65°C. The reaction mixture containing the salt is then acidified with dilute hydrochloric acid and evaporated to remove solvent. The desired product is extracted into chloroform, and the chloroform is evaporated to obtain the product.

When 6-fluoro-2-methyl-1-3-(p-methylsulfinylbenzylidene)-indanone or 6-fluoro-2-methyl-3-(p-methylthiobenzylidene)-indanone is used

instead of 6-fluoro-2-methyl-lindanone in the above example, the corresponding inoenylacetic acid compound is obtained in a similar way.

When dilithioacetate obtained from example 2, lithio-acetonitrile, lithio-dimethylacetamide or lithio-methylacetate obtained from example 35 are used instead of lithio-sodium acetate in the above example, 5-fluoro-2-methyl-indenyl-3-acetic acid, 5-fluoro-2 -methyl-indenyl-3-acetonitrile, N,N-dimethyl-5-fluoro-2-methyl-indenyl-3-acetamide or methyl 5-fluoro-2-methyl-indenyl-3-acetate.

Example 7

t-butyl-5-fluoro-2-methyl-1-(pro-ethylthiobenzylidene)-indenyl-3-acetate To a solution of 0.002 mol of 5-butyl-5-fluoro-2-methylinden-3-acetate and 0.00 /+ mol of p-methylthiobenzaldehyde in 3 ml of anhydrous pyridine is added to 1.639 of a 40% solution of benzyltrimethylammonium hydroxide ("Triton B") in methanol. The resulting solution is stirred at room temperature overnight.

The reaction mixture is poured into a mixture of ice and water, acidified with 2.5 N hydrochloric acid and extracted with ether. The ether solution is then washed with 2.5 N hydrochloric acid, then with water until neutral, dried over sodium sulphate and evaporated in vacuo.

When methyl-5-fluoro-2-methyl-indenyl-3-acetate, 5-fluoro-2-methyl-indenyl-3-acetonyl or N,N-dimethyl-5-fluoro-2-methyl-indenyl - 3-acetamide is used instead of t-butyl-5-fluoro-2-methyl-inden-3-acetate in the above example, the corresponding benzylidene methyl ester, -acetonitrile or -acetamide is obtained in a similar way.

Example 8

5- fluoro - 2 - met, hy 1- 1 - (p- methylsulf inylbenzylidene) - indenyl - 3 - acetic acid

A mixture of 0.1 mole of methyl-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-acetate and 200 ml of 1N sodium hydroxide is heated under reflux under nitrogen with stirring for 30 minutes. The mixture is cooled, diluted with water and acidified with 50% acetic acid. The mixture is filtered, and the precipitate is washed with water and dried in air at 25°C.

When methyl-5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-indenyl-3-acetate is used instead of the indenyl compound in the above example, 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)~indenyl- 3-acetic acid.

Example 9

5- fluoro- 2- methyl- 1-( p- methyl sulf inyl b en z y1idene)- indeny1- 3- ed dix yre

0.0422 mol of sodium metaperiodate trihydrate in S, 5 ml of water is added to 0.01 mol of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-indenyl-3-acetic acid in 20 ml of methanol and 10 ml of acetone at room temperature . The mixture is stirred overnight and then evaporated to a small volume, diluted with water and filtered. The precipitate is washed with water and dried in air.

Example 10

5- fluoro- 2- methyl- 1-( p- methylsulfinylbenzylidene)- indenyl- 3- acetic acid

0.01 mol of t-butyl 1-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-acetate in 30 ml of toluene is heated at 90° C. for 3 hours with 3 mmol of toluenesulfonic acid. The solution is washed with water while hot, and then evaporated in vacuo to give the product.

Example 11

5- fluoro- 2- methyl- 1-( p- met hylsulfinylbenzylidene) rindenyl- 3- acetic acid

0.1 mol of N,N-dimethyl-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-acetamide is heated under reflux in 100 ml of methanol with 15 g of sodium hydroxide until the evolution of dimethylamine in the significant ceases. The mixture is cooled, diluted with water and acidified with hydrochloric acid, whereby 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-acetic acid is obtained, which is filtered off.

When N,N-dimethyl-5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-indenyl-3-acetamide, 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-indenyl-3-acetonitrile or 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-acetonitrile is used instead of the acetamide compound in the above example, the corresponding indenyl dioxides are obtained.

Example 12

5- fluoro- 2- methyl- 1-( p- methylsulfinylbenzylidene)- indenyl-3- acetic acid

To a solution of 40 mmol of lithium diisopropylamide in 150 ml of tetrahydrofuran at -78°C, 40 mmol of ethyl trimethylsilyl acetate is added over the course of 15 minutes. While maintaining the same temperature, 40 mmol of 6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan-1-one are added with stirring as a 20% solution in tetrahydrofuran. The reaction mixture is allowed to reach ambient temperature, then heated at 40°C for 6 hours. After 6 hours, 50 ml of water is added, and the reaction mixture is heated under reflux for a further 2 hours. After adding sufficient hydrochloric acid to bring the pH to 2, the tetrahydrofuran is crystallized in vacuo, and the product is collected and washed in a funnel with water and dried.

When 6-fluoro-2-methyl-3-(p-methylthiobenzylidene)-indan-1-one or 6-fluoro-2-methyl-1-indanone is used instead of 6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene )~indan-l-one in the above example, the corresponding 3-indenylacetic acids are obtained.

Example 13

5- fluoro- 2- methyl- 3- indenylacetic acid

To a solution of one equivalent of α-dibenzylphosphonoacetic acid

in 200 ml of tetrahydrofuran is added at -80°C a solution of two equivalents of lithium diisopropylamide in 100 ml of tetrahydrofuran. The reaction mixture is stirred for 20 minutes, then an equivalent of 6-fluoro-2-methyl-1-indanone is added, the temperature being kept below -70°C.

After a further 1/2 hour, the reaction temperature is gradually raised and kept at 40°C overnight. Water is added, and the tetrahydrofuran is removed in vacuo. The aqueous solution is extracted with toluene, and the toluene is discarded. The desired product is crystallized by careful addition of hydrochloric acid to pH 2. It is collected by filtration and washed with water and then dried.

When 6-fluoro-2-methyl-3-(p-methylthiobenzylidene)-indanone or 6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan-1-one is used instead of 6-fluoro- .2-methyl-1-indanone, the corresponding 3-indenyacetic acids are obtained.

Claims (11)

1. Procedure for the production of 5-fluoro-2-methyl-1-(p-methyl-sulfin <y> lb enz <y> lid en)-inden-3-acetic acid, characterized by the steps that: (a) an indanone of the formula: where R 3 is methylthio or methylsulfinyl, is reacted with a lithium compound of the formula: where X is COOR, CN or CON where R1 and R2 are each alkyl, aryl, <R>l<R>2 aralkyl or substituted alkyl, substituted aryl or substituted aralkyl; or R 1 and R 2 together may be cycloalkyl and R is hydrogen, alkyl, alkali or alkaline earth metal; and Y is hydrogen, -Si(R^ )^ or ~ jj5 ~ (OR) 2 where R^ is alkyl, phenyl or benzyl, or substituted alkyl, substituted phenyl or substituted benzyl, followed by dehydration to form an indene compound; (b) in the case of compound (I), the p-methylsulfinyl or p-methylthio-benzylidene group is introduced into the I-position of the indene; (c) and when R is alkyl, alkali or alkaline earth metal, the product is hydrolyzed, or, if desired, pyrolyzed when R is t-butyl, the compound of step (a) when the indanone is compound (II) or the product of step (b) ; and (d) when R 1 is methylthio, there is oxidized before or after steps (b) or (c). 2. Method according to claim 1, characterized in that a compound is used where X is COOR and R is t-butyl or alkali or alkaline earth metal. 3. Method according to claim 2, characterized in that R is t-butyl. 4- Method according to claim 2, characterized in that R is alkali or alkaline earth metal. 5. Method according to claim 1, characterized in that in step (b) the indene is condensed with p-methylsulfinylbenzaldeh3'd under basic conditions. 6. Method according to claims 2-4, characterized in that an indanone of formula (I) is used and that in step (b) the indene is condensed with p-raethylsulfinyl-benzaldehyde under basic conditions. 7- Procedure for the production of 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid, characterized by the steps that: (a) 6-fluoro-2-methyl-1-indanone is reacted with a lithium enolate compound of the formula: Li - CH2 - COOR where R is alkyl, aralkyl or alkali or alkaline earth metal, to form a hydroxyindene compound which is dehydrated to the corresponding indene; (b) the resulting indene is condensed with p-methylthiobenzaldehyde to form the 1-p-methylthiobenzylidene-indene-acetic acid compound; (c) the obtained indene-acetic acid compound is hydrolyzed when R in step (a) is alkyl or aralkyl, and acidified when R is alkali or alkaline earth metal, to form the free indene-acetic acid compound, and (d) the obtained indene-acetic acid compound is oxidized to the desired product or the indene-acetic acid compound is oxidized before step (c). 8- Method according to claim 7, characterized in that R is t-butyl or alkali or alkaline earth metal. 9- Method according to claim 1, characterized in that Y is -P-(OR1 )2 and X is COOM, O where M is hydrogen, alkali or alkaline earth metal. 10. Method according to claim 1, characterized in that Y is -Si^^)^ where R^ is C1^-alkyl, phenyl or benzyl, and X is COO-alkyl. 11. Method according to claim 1, characterized in that R 3 is p-methylthio, and the oxidation is carried out as the last step.