ITMI960500A1 - PROCEDURE FOR THE PREPARATION OF ALPHA-ARYLPROPIONIC ACIDS AND RELATED INTERMEDIATES - Google Patents

Description

Description of the industrial invention entitled: "PROCEDURE FOR THE PREPARATION OF ALPHA-ARYLPROPION CI AND RELATIVE INTERMEDIATES"

The present invention relates to the preparation of compounds of pharmaceutical interest, in particular? -Arylpropionic acids.

Background of the invention

The class of? -Arylpropionic acids (APAs) is of great importance in the pharmaceutical sector as it includes several terms used as effective anti-inflammatory drugs, belonging to the group of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Generally these acids are included in the formula

where * C? a chiral carbon atom and Ar? a possibly substituted aromatic residue.

Among the APAs can be mentioned, in particular, Naproxen (Ar = 2- (6-methoxy) naphthyl), ketoprofen (Ar = 3-benzoliphenyl), and ibuprofen (Ar = 4-isobutylphenyl), which cover large part of the NSAID market. Numerous studies have been carried out on? -Arylpropionic acids and just as numerous are ongoing research. Among the problems faced, the most? important concern: i) various aspects of a pharmacological nature deriving from chirality? of aarylpropionic acids; ii) the development of new synthetic processes suitable for the preparation of both racemic forms and eutomers. In relation to the first point it should be noted that in the case of aarylpropionic acids? it has been established that, in all cases, the active enantiomers (eutomers) belong to the S series; the enantiomers belonging to the R series are not per se? active; however, in some cases,? It has been found that, depending on their structure, they can convert "in vivo" into active isomers, with a degree of conversion that cannot be measured with precision and, in any case, varies from species to species and from individual to individual belonging to the same species. Other research is aimed at identifying any interference or harmful effects of APAs in the R form.

The discovery of new procedures that are less expensive than those used up to now? still a necessity? felt in the chemical and pharmaceutical industry.

Taking into account what is expressed in the first point in relation to the uncertainties existing on the possible collateral actions (antagonistic or perhaps even harmful) of the enantiomers belonging to the R series,? Also of interest is the development of procedures that allow the obtainment of the S enantiomers free or almost free from the R enantiomers.

The preparation of ibuprofen through the hydrolysis of the corresponding methyl thiol ester is known (Japanese Patent Application Publication No. 78-50137). The thiol ester? obtained by treatment with 1-methylthio-1-methylsolfinyl-2- (4-isobutylphenyl) propene acids, in turn prepared by reaction between LiCH (SCH3) (SOCH3) and 1-acetoxy-lysobutylphenylethane (obtained by reduction and subsequent acetylation of 4-isobutylacetophenone) and treatment of l-methylthio-l-methylsulfinyl-2-acetyl-2-isobutylphenylpropane cos? obtained with potassium tert-butylate.

Russel and Ochrymowycz (J.O.C., 35 (3), 4970, 764-770) describe the obtainment of S-meth? L phenylthioacetates, possibly a-substituted by the hydration of ketene thioacetals.

Seebach and BUrstinghaus (Synthesis, July 1975,461-2) prepare S-methylphenylthiopropionate from acetophenone and bis (methylthio) -trimethylsilylmethyllithium and subsequent hydrolysis of thioacetal ketene.

Russel and Ochrymowycz (ibid.) Indicate? '? - keto trimethyl trithioorthester RC0C (8013) 3 as an intermediate useful for obtaining a-keto thiol esters and esters of a-hydroxy acids.

Barbero et al. (J. Chem. Soc. Perkin Trans. I, 1993, 2075-2080) illustrate the synthetic applications of tris (methylthio) methyllithium in the preparation of aliphatic methyl thiol carboxylates from the corresponding halides.

Description of the invention

It has now been found that the use of an aarylpropionic acid thiol ester of interest, obtained through a particular preparation method, allows to obtain the final products with very high yields.

Therefore ? an object of the present invention a process for the preparation of? -arylpropionic acids of formula (I)

where Ar? the residue of an aromatic hydrocarbon having from 6 to 10 carbon atoms, possibly substituted with one or more? alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, heteroaryl, halogen groups; which includes the following stages:

a) reaction between an active derivative at the nucleophilic acyl substitution of an aromatic carboxylic acid Ar-CO-X; where X? selected from halogen, alkylthio, alkoxy, aryloxy;

and tris (alkylthio) methylthio

where R 1 is the residue of a linear or branched alkyl having from 1 to 6 carbon atoms or of an arylmethyl, to give the corresponding trithioortoester (II)

b) isomerization of? - keto trithioortoester in the presence of an acid, protic or non-protic, in anhydrous conditions to give the corresponding to,? - dialkylthio thiol ester (III)

c) subsequent methyl-de-alkylthiolation to give the corresponding amethyl-a-alkylthio thiol ester (IV)

where Ar and R ^ are as defined above;

d) subsequent proto-de-alkylthiolation to give the thiol ester (V)

where Ar is? they are as defined above;

e) alkaline hydrolysis of the thiol ester.

Another object of the present invention is the use of the compound of formula (III)

as an intermediate in the above procedure.

A further object of the present invention is a process for the enantiomeric resolution of racemic? -Arylpropionic acid.

The present invention allows to obtain the aarylpropionic acids of interest, in particular those of pharmaceutical use, with high yields and using as starting compounds esters of aromatic carboxylic acids and commercially available or easily prepared reagents.

These and other objects of the present invention will now be described in detail and illustrated also with examples of preparation. Detailed description of the invention

Examples of aryl are phenyl and naphthyl, possibly substituted in the different positions by one or more? substituents selected from halogen, for example fluorine, chlorine, bromine, iodine; alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and relative isomers; alkoxy, aryloxy, alkanoyl, aroyl, heteroaryl. Example of arylmethyl? benzyl.

Among the meanings of Ar, phenyl, 2-naphthyl, 4-isobutylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-methoxyphenyl, 6-methoxy-2-naphthyl, 3-benzoylphenyl are particularly preferred.

In particular, the preparation of the thiol ester? illustrated by the following Scheme 1:

Scheme 1

where are they as defined above, R3? lower alkyl.

Obtaining? -Keto trithioorthesters starting from esters of aromatic carboxylic acids (1st stage)? described in J. Org. Chem., 1995, 60, 6017-6024, where the reaction mechanism between esters of carboxylic acids and tris (methylthio) methillithio is studied. In J. Chem. Soc. Perkin Trans. 1, 1993, 2075-2080? reported the synthetic application of tris (methylthio) methylthio in the preparation of aliphatic methyl thiol carboxylates from the corresponding alkyl halides.

Surprisingly yes? found that the transformation of the starting aromatic carboxylic acid ester into? -keto trithioortoester and the subsequent isomerization also take place with tris (alkyithium) methyl lithium in which the alkyl? higher than methyl. The results more? favorable are achieved with the terms ethyl and butyl.

Another surprising aspect of the process described in Scheme 1? that not only the esters of aromatic carboxylic acids, but also pi? in general, the derivatives pi? active in the nucleophilic acyl substitution of these acids, such as halides, thiol esters and anhydrides.

Advantageously, tris (methylthio) methyllium? prepared starting from tris (methylthio) methane with a method described in J. Chem. Soc. Mentioned above which avoids the use of methyl mercaptan, the drawbacks of which are well known. Furthermore, in stage 3, the methyl mercaptan that is released remains in the aqueous phase as a potassium salt and can? be easily destroyed by oxidation or, alternatively, recovered and used for stage 4. In stage 4, the methylthio group, which is released as MeS <+>, reacting with MeS <? > d? origin to dimethyl disulfide and therefore, even in this stage, it is not released? of methyl mercaptan. Equally advantageously, tris (alkylthio) methylthio are prepared starting from the corresponding tris (alkylthio) methanes with a procedure similar to that used for the preparation of tris (methyl) methylthio. In particular, the tris (butylthio) methyllium pu? be advantageously prepared also from dibutyl trithiocarbonate and butylithium. Stages 3 and 4 are carried out starting from the trialkyl trithio orthoesters with procedures similar to those used starting from the trimethyl trithio orthoesters.

It has been surprisingly found that? '? - keto trithioortoester (II), in the presence of a protic or non-protic acid, under anhydrous reaction conditions, isomerizes to?,? - dialkylthio thiol ester, an important intermediate that allows to obtain acids ? -arylpropionics with few and convenient synthetic steps.

According to the present invention, by acid, as used in stage 2, is meant a protic acid or a non-protic acid. It is essential that the Sicilian reaction conditions are anhydrous, why? in non-anhydrous conditions, keto-thiol esters are formed, of no use. for the purposes of the present invention.

The anhydrous reaction conditions are normally obtained by the technician with normal experience, who will know find the conditions and the means more? suitable, such as the use of anhydrous solvents, inert atmosphere, and suitable devices for the protection of the reaction environment.

As an example of a reaction carried out with aprotic acids, one can? cite the triphenylmethyl (trityl) cation, in saline form. Examples of protic acids according to the present invention are methanesulfonic acid, ptoluenesulfonic acid, tetrafluoboric etherate. Isomerization conducted with protic acids? preferred as less expensive and why? provides the isomerization product which does not require purification.

As for stage 3 of scheme 1, methylation? conducted according to procedures known to the expert in the field. Basic dog? potassium tert-butylate is preferred. Methylating agents are for example dimethyl sulfate, dimethyl carbonate, methyl acetate, MeAlg.

As for stage 4 of scheme 1, the protodealkylthiolation? likewise conducted according to procedures known to the skilled in the art through the use of a mercaptide. Sodium mercaptide is preferred.

The alkaline hydrolysis reaction? conducted with completely conventional procedures and known to the expert in the sector. The thiol ester, optionally dissolved in a suitable solvent, for example a ketone, such as acetone, and preferably a solvent miscible with water, is treated with an aqueous alkaline solution, for example 10% w / v potassium hydroxide. The reaction temperature is not? criticism, even if? heating between room temperature and reflux temperature is preferable. The reaction time can? be determined as a function of the reaction conditions, for example by checking their progress.

The process according to the present invention leads to the racemic mixture of? -Arylpropionic acid. Therefore, ? also included in the present invention is a process for obtaining aarylpropionic acids which involves the transformation of the thiol ester of formula (V)

where Ar e are defined above in an ester or amide of a chiral alcohol or amine, separation of the diastereoisomers and hydrolysis of the corresponding ester or amide of the enantiomer of interest. The resolution of racemic mixtures in enantiomers via formation of diastereomers? well known and commonly used method. In the case of? -Arylpropionic acids (APAs), the corresponding thiol esters can, by this way, provide the enantiomers of pharmaceutical interest (S) and can also? supply the non-active or less active enantiomers (R), which can be subjected to racemization and recycling.

The process according to the present invention? of applicability? in general, however, in some cases where functional groups sensitive to the reaction conditions are present, these must be suitably protected.

For example, in the case of ketoprofen, or 2- {3-benzoyl) phenylpropionic acid,? it is advisable to protect the carbonyl in the course of obtaining the thiol ester.

It was found that the protection of the carbonyl group? appropriate to take place on the starting conpo according to the following stages:

a) transformation of the carbonyl group of the compound of formula (VI)

where R2? a lower alkyl group, in the corresponding ketal; b) subsequent obtaining of the corresponding? -keto trithioortoester; c) restoration of the carbonyl group;

d) subsequent transformation into the corresponding thiol ester as described above for the preparation of the thiol ester.

Within the scope of the present invention? A process has also been found for obtaining the ester of 4-isobutylbenzoic acid, the starting compound for obtaining the thiol ester of formula (V) where Ar? 4-isobutylphenyl, and the? -Arylpropionic acid obtained? 3? (4? isobutyl) phenylpropionic acid or ibiprofen.

According to the present invention, said ester is prepared by reaction of isobutylbenzene with oxalyl dichloride and subsequent treatment with methanol, or other suitable alcohol, to give the relative ester. Thereafter, the thiol ester is obtained as described above.

In case Ar? 2- (6-methoxy) naphthyl, the process according to the invention provides for 6-methoxy-2-naphthoic acid, not commercially available, therefore? It is necessary to start from 6-methoxy-2-naphthonitrile, a very expensive reagent.

It has been found that the thiol ester of formula (V) where Ar? 2- (6methoxy) naphthyl pu? be prepared with a method pi? which includes the following stages:

a) treatment of an ester of formic acid with tris (alkyl) methyl lithium to give the corresponding trithioortoester;

b) subsequent isomerization to give the corresponding a, a-dialkylthio thiol ester;

c) subsequent methylation to give the corresponding?,? dialkylthiopropantioate of S-alkyl;

d) Friedel-Crafts reaction with said thiol ester of 2-methoxynaphthalene.

Alternatively,? '?,? - S-alkyl dialkylthiopropantioate, to be used in the Friedel-Crafts reaction, can? be obtained by reaction of an alkyl acetate with tris (alkylthio) methylthio to give the trithioortoester, and subsequent isomerization.

Said method, in addition to providing good results in the case of Naproxen,? of applicability? general for the purposes of the present invention.

The following examples further illustrate the invention.

For clarity, the compounds prepared in the examples are indicated with respect to the general formula and Reaction Scheme 1 reported above as follows:

Preparations

Methyl 4-isobutylbenzoate

The corresponding acyl chloride is first prepared, following the procedure described in Helvetica Chimica Acta, vol. 65, Phase. 8 (1982), Nr. 241, 2448-2449 which is then converted into the corresponding ester by reaction with methanol with a yield of 92% (kp = 80-81 C at 0.3 mm of Hg). % NMR: 0.88 ppm (d, J = 6, 2CH3), 1.65-2.10 (m, CH), 2.48 (d, J = 7, CH2), 3.80 (s, OCH3 ), 7.05-7.80 (2d, J = 8.4Harom).

Methyl 6-Methoxy-2-naphthoate

The 6-methoxy-2-naphthonitrile (commercial product) was first hydrolyzed in the basic medium into the corresponding carboxylic acid (96%). then carried out an esterification with methanol in the presence of methanesulfonic acid (90%); m.p. = 131-2 <e> C (CHC13). ? NMR: 3.75 and 3.78 ppm (2s, 20CH3), 6.82-7.10.7.38-7.95 and 8.20-8.40 (3m, 2: 3: 1,).

to complete esterification. It is cooled to room temperature, trimethyl orthoformate (10 ml) is added and stirring is maintained until methyl 3-benzoylbenzoate disappears (24 hours). The mixture is treated with aqueous sodium bicarbonate and extracted with ethyl ether (2 x 50 ml). The combined organic extracts are washed with water (2 x 100 ml), anhydrified and the solvent evaporated under vacuum. Practically pure methyl 3- (phenyldimethoxymethyl) benzoate is obtained with a yield of 94% (2.70 g). The compound, crystallized from carbonpentane tetrachloride, has m.p. 89-90? C. ? NMR: 3.02 ppm (s, 2 OCH3), 3.78 (s, COOCH3), 7.05-7.90 and 8.00-8.12 (2m, 8: 1, ?? ^^).

3) The 2,2,2-tris (methylthio) -1- (3-benzoyl) phenylethanone? was obtained by hydrolysis of the compound obtained in the previous point 2) (4.08 g, 10 mmol) with conc. (2.04 g, 20 mmol) in ethyl ether (20 ml). The reaction ? complete after 1 hour of stirring at room temperature. The reaction mixture is diluted with ethyl ether (200 ml), neutralized with solid sodium bicarbonate, washed with water (2 x 100 ml) and dried. After evaporation of the solvent under vacuum, the practically pure product is obtained with a yield of 93% (3.37 g).

Trityl perchlorate (0, 51 g, 1.5 mmol) under stirring and under nitrogen flow. The color of the solution immediately turns red and tends to darken over time. After two hours of stirring at room temperature, TLC controls (S1O2; eluent: petroleum ether / acetone, 9.5: 0.5) and GC-MS show the disappearance of the starting compound and the presence of two products: the ( methylthio) triphenylmethane and S-methyl 2-phenyl-2,2-bis (methylthio) thioacetate. The reaction mixture is poured into a 5% aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic phase is washed with water and dried with sodium sulphate. The crude residue obtained from the evaporation of the solvent under vacuum is chromatographed on a silica gel column (eluent: petroleum ether / acetone, 9.5: 0.5).

Bianchetti Giuseppe and others

Methanesulfonic acid (0.5 g, 5 mmol) is added to a solution of 1,1-tris (methylthio) -2-phenylethanone (2.58 g, 10 mmol) in anhydrous methylene clonyrum (25 ml). ), under stirring and under nitrogen flow. After two hours of stirring at room temperature, TLC controls (S1O2; eluent; petroleum ether / acetone, 9.5: 0.5) and GC-MS show the disappearance of the starting compound and the presence of a single product. The reaction mixture is poured into a 5% aqueous solution of sodium bicarbonate and extracted with methylene chloride. The combined organic extracts are washed with water and dried with sodium sulphate. The crude residue obtained after evaporation of the solvent under vacuum,? 2-phenyl-2,2-bis (methylthio) thioacetate of S-methyl, practically pure (2.38 g, 92%).

A solution of 2-phenyl-2,2-bis ( S-methyl methylthio) thioacetate (2.58 g, 10 mmol) in anhydrous THF (3 ml). The solution immediately takes on a golden yellow color. After stirring for 10 minutes at room temperature, dimethyl sulfate (1.51 g, 12 mmol) in anhydrous THF (2 ml) is quickly added. After 30 minutes, GC and TLC controls (S? O2; eluent: petroleum ether / ethyl ether, 9.8: 0.2) show the disappearance of the starting compound. The reaction mixture poured into water is neutralized with concentrated hydrochloric acid. It is extracted with ethyl ether. The organic phase is washed with water (100 ml) and dried with sodium sulphate. The crude residue obtained from the evaporation of the solvent under vacuum is chromatographed on a short column of silica gel (eluent: petroleum ether / ethyl ether, 9.8: 0.2). S-methyl 2-phenyl-2- (methylthio) thiopropionate (2.05 g, 91%) is obtained.

The same solvent mixture (petroleum ether / diethyl ether, 9.8: 0.2)? was used for the purification of Ar = b, c, d, f.

The eluent used for the purification of Ar = e, g, h? Petroleum ether / diethyl ether, 4: 1.

A solution of 2-phenyl-2- (methylthio) thiopropionate of S. -methyl (2.26 g, 10 mmol) in the same solvent (5 ml). The solution takes on a pale yellow color. After 1 hour of stirring at room temperature, GC and TLC controls (S? O2; eluent: petroleum ether / ethyl ether, 9.8: 0.2) show the disappearance of the starting compound. The reaction mixture is poured into water and neutralized with concentrated hydrochloric acid. It is extracted with ethyl ether. The organic phase is washed with water (100) and dried with sodium sulphate. After evaporation of the solvent under vacuum, practically pure S-methyl 2-phenylthiopropionate is obtained (1.75 g, 97%. This compound is used directly in the next step).

The two enantiomers of the hydratropic acid thiol ester were identified by GC, using a chiral stationary phase column. In a test conducted on the racemic thiol ester operating with CD3SOCD2Na in CD3SOCD3, yes? had immediate H / D exchange and this result, obviously, constitutes proof, albeit indirect, of the possibility? racemization of the R enantiomer.

Example 7

To a solution of S-methyl 2-phenylthiopropionate (1.80 g, 10 mmol) in acetone (10 ml), an aqueous solution of 10% potassium hydroxide (1.20 g, 20 mmol). It is heated with a slight reflux for 2 hours, until? the TLC control (S? O2; eluent: petroleum ether / ethyl ether, 9.8: 0.2) indicates the disappearance of the starting compound. It is cooled and acidified carefully with concentrated hydrochloric acid. The reaction mixture is extracted with ethyl ether and the organic phase is dried with sodium sulphate. After evaporation of the solvent under vacuum, practically pure 2-phenylpropionic acid (hydratropic acid) is obtained (1.50 g, 100%).

The reactions carried out and the yields of the single stages are summarized in Table 1.

Table 2

Table 6

Claims (8)

1. Process for the preparation of? -Arylpropionic acids of formula (I) where Ar? the residue of an aromatic hydrocarbon having from 6 to 10 carbon atoms, possibly substituted with one or more? alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, halogen groups; which includes the following stages: a) reaction between an active derivative at the nucleophilic acyl substitution of an aromatic carboxylic acid Ar-CO-X; where X? selected from halogen, alkylthio, alkoxy, aryloxy; and trialkylthiomethyl lithium where is it ? the residue of a linear or branched alkyl having from 1 to 6 carbon atoms or of an arylmethyl, to give the corresponding trithioorthester (II) b) isomerization of the trithioortoester in the presence of an acid, protic or non-protic, in anhydrous conditions to give the corresponding?,? - dialkyl thiol ester (III) c) subsequent methyl-de-alkylthiolation to give the corresponding amethyl-a-alkylthio thiol ester (IV) where Ar and R1_are as defined above; d) subsequent proto-de-alkylthiolation to give the thiol ester (V) where Ar is? they are as defined above; e) alkaline hydrolysis of the thiol ester. 2. Process according to claim 1, in which Ar? selected from the group consisting of phenyl, 2-naphthyl, 4-isobutylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-methoxyphenyl, 6-methoxy-2-naphthyl, 3-benzoylphenyl. 3. Use of the compound of formula (III) where Ar? the residue of an aromatic hydrocarbon having from 6 to 10 carbon atoms, possibly substituted with one or more? alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, halogen groups; And ? ? the residue of a linear or branched alkyl having from 1 to 6 carbon atoms as an intermediate in the process of claim 1. 4. Process for obtaining enantiomers of aarylpropionic acids of formula (I) where Ar? the residue of an aromatic hydrocarbon having from 6 to 10 carbon atoms, possibly substituted with one or more? alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, halogen grapples; which includes the transformation of the thiol ester of formula where Ar? as defined above and R1? the residue of a linear or branched alkyl having from 1 to 6 carbon atoms, in an ester or amide of a chiral alcohol or amine, resolution of the diastereomeric mixture and hydrolysis of the ester or amide of the enantiomer of interest. 5. Process according to claim 1, in which Ar? 3-benzoylphenyl, characterized in that said thiol ester? prepared according to the following stages: a) transformation of the carbonyl group of the compound of formula (VI) where R2? an alkyl group, in the corresponding ketal; b) subsequent obtaining of the corresponding trithioortoester; c) restoration of the carbonyl group; d) subsequent transformation into the corresponding thiol ester according to steps c) and d) of claim 4. 6. Process according to claim 1, in which Ar? 4-isobutylphenyl, characterized in that said thiol ester (V)? prepared according to the following stages: a) reaction of isobutylbenzene with oxalic acid dichloride and subsequent treatment with methanol to give the methyl ester of 4-isobutylbenzoic acid; b) obtaining the desired product by transforming said ester obtained in step a) into the corresponding thiol ester according to claim 4. 7. Procedure for the preparation of the compound of formula (V) where Ar? the residue of an aromatic hydrocarbon having from 6 to 10 carbon atoms, possibly substituted with one or more? alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, halogen groups; R1? the residue of a linear or branched alkyl having from 1 to 6 carbon atoms or of an aryl methyl, which includes the following steps: a) treatment of an ester of formic acid with tris (alkylthio) methyl lithium to give the corresponding triortoester; b) subsequent isomerization to give the corresponding a-ketodithioacetal; c) subsequent methylation to give the corresponding?,? dialkylthiopropantioate of S-alkyl; d) Friedel-Crafts reaction with said thiol ester of Ar-H, where Ar? as defined above. 8. Procedure for the preparation of the compound of formula (V) where Ar? the residue of an aromatic hydrocarbon having from 6 to 10 carbon atoms, possibly substituted with one or more? alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, halogen groups; ? ? the residue of a linear or branched alkyl having from 1 to 6 carbon atoms or of an arylmethyl, which comprises the following steps: a) treatment of an ester of acetic acid with tris (alkylthio) methyl lithium to give the corresponding triortoester; b) subsequent isomerization to give the corresponding a-ketodithioacetal; c) Friedel-Crafts reaction with said thiol ester of Ar-H, where Ar? like above