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WO1997034860A1 - PROCEDE DE PREPARATION D'ACIDES α-ARYLPROPIONIQUES ET DE LEURS INTERMEDIAIRES - Google Patents

PROCEDE DE PREPARATION D'ACIDES α-ARYLPROPIONIQUES ET DE LEURS INTERMEDIAIRES Download PDF

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Publication number
WO1997034860A1
WO1997034860A1 PCT/EP1997/001258 EP9701258W WO9734860A1 WO 1997034860 A1 WO1997034860 A1 WO 1997034860A1 EP 9701258 W EP9701258 W EP 9701258W WO 9734860 A1 WO9734860 A1 WO 9734860A1
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WO
WIPO (PCT)
Prior art keywords
thiol ester
ester
give
residue
alkyl
Prior art date
Application number
PCT/EP1997/001258
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English (en)
Inventor
Iacopo Degani
Stefano Dughera
Rita Fochi
Original Assignee
Consiglio Nazionale Delle Ricerche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Consiglio Nazionale Delle Ricerche filed Critical Consiglio Nazionale Delle Ricerche
Priority to AU20268/97A priority Critical patent/AU2026897A/en
Publication of WO1997034860A1 publication Critical patent/WO1997034860A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides

Definitions

  • the present invention relates to the preparation of pharmaceutically interesting compounds, particularly ⁇ - arylpropionic acids.
  • APAs ⁇ -arylpropionic acids
  • a great number of studies have been carried out about ⁇ -arylpropionic acids and as many researches are in progress.
  • the most important relate to: i) various aspects of pharmacological nature deriving from the chirality of ⁇ -arylpropionic acids; ii) the accomplishment of novel preparation processes suitable to the preparation of both racemic and eutomeric forms.
  • the enantiomers (eutomers) of the S series proved to be always the active ones; the enantiomers belonging to the R series are not pgr se active; however, in some cases, depending on their structure, they have been found to be capable of converting in vivo into the active isomers, with a conversion degree which cannot be measured precisely and can vary among species and individuals belonging to the same species.
  • Other researches are aimed at finding any interferences or adverse effects of APAs in the R form.
  • the preparation of ibuprofen through hydrolysis of the corresponding methyl thiol ester (Japanese published Patent application n. 78-50137) is known.
  • the thiol ester is obtained treating with acids 1-methylthio-1- nvethylsulfinyl-2-(4-isobutylphenyl)propene, in its turn prepared by reaction of LiCH(SCH 3 ) (SOCH 3 ) with 1- acetoxy-1-isobutylphenylethane (obtained by reduction and subsequent acetylation of 4-isobutylacetophenone) and treatment of the resulting 1-methylthio-1- methylsulfinyl-2-acetyl-2-isobutylphenylpropane with potassium tert-butylate.
  • Russel and Ochrymowycz disclose the preparation of optionally ⁇ - substituted S-methyl phenylthioacetates by hydrolysis of ketene thioacetals.
  • Russel and Ochrymowycz disclose ⁇ -keto trimethyl trithioorthoester RCOC(SCH 3 ) 3 as a useful intermediate for the preparation of ⁇ -keto thiol esters and ⁇ -hydroxyacid esters.
  • an object of the present invention is a process for the preparation of ⁇ -arylpropionic acids of formula (I)
  • Ar-CO-X reactive to acyl nucleophilic substitution; wherein X is selected from halogen, alkylthio, alkoxy, aryloxy;
  • R 1 is the residue of a C 1 -C 6 straight or branched alkyl or of an arylmethyl, to give the corresponding trithioorthoester (II)
  • the present invention allows to obtain the desired ⁇ -arylpropionic acids, particularly those for the pharmaceutical use, in high yields and using aromatic carboxylic acid esters and commercially available or easy-to-prepare reagents as the starting compounds.
  • aryl group examples include phenyl and naphthyl, optionally substituted at the different positions with one or more substituents selected from halogen, such as fluorine, chlorine, bromine, iodine; alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and related isomers; alkoxy, aryloxy, alkanoyl, aroyl, heteroaroyl.
  • halogen such as fluorine, chlorine, bromine, iodine
  • alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl and related isomers
  • alkoxy, aryloxy, alkanoyl, aroyl, heteroaroyl alkoxy, aryloxy, alkanoyl, aroyl, heteroaroyl.
  • arylmethyl is benzyl.
  • R 3 is lower alkyl
  • tris(methylthio)methyllithium is prepared starting from tris(methylthio)methane with a method described in J. Chem. Soc. cited above, which avoids the use of methyl mercaptan, which drawbacks are well known.
  • step 3 the formed methyl mercaptan remains in the aqueous phase as a potassium salt and can easily by destroyed by oxidation or alternatively it can be recovered and used in step 4.
  • the methylthio group which is formed as MeS + , reacts with MeS- to give dimethyl disulfide and therefore also in this step no methyl mercaptan is released.
  • Tris(alkylthio)methyllithiums are prepared advantageously also starting from the corresponding tris(alkylthio)methanes with a procedure similar to that used for the preparation of tris(methylthio)- methyllithium.
  • tris(butylthio)methyl- lithium can advantageously be prepared also from dibutyl trithiocarbonate and butyllithium.
  • the steps 3 and 4 are carried out starting from the trialkyl trithioorthoesters with processes analogues to those used starting from the trimethyl trithioortho esters.
  • ⁇ -keto trithioorthoester (II) in the presence of a protic or aprotic acid, in anhydrous reaction conditions, isomerizes to ⁇ , ⁇ -dialkylthio thiol ester, an important intermediate which allows to obtain ⁇ -arylpropionic acids with few, convenient synthetic steps.
  • a protic or aprotic acid is meant. It is mandatory for reaction conditions to be anhydrous, since in not anhydrous conditions ⁇ -keto thiol esters form, which are useless to the purposes of the present invention.
  • Anhydrous reaction conditions are usually obtained by those skilled in the art, who will be able to find the most appropriate conditions and means, such as the use of anhydrous solvents, inert atmosphere and adequate means for the protection of the reaction environment.
  • aprotic acids the triphenylmethyl (trityl) cation in the salt form can be cited.
  • protic acids according to the present invention are methanesulfonic acid, p-toluenesulfonic acid, tetrafluoroboric acid-ethyl ether complex.
  • the isomerization carried out with protic acids is preferred in that it is less expensive and it yields an isomerization product which needs no purification.
  • step 3 of scheme 1 the methylation is carried out according to procedures known to those skilled in the art. Potassium tert-butylate is preferred as the base.
  • Methylation agents are, for example, dimethyl sulfate, dimethyl carbonate, methyl acetate, MeAlg.
  • step 4 of scheme 1 the proto-de-alkylthiolation is carried out as well according to procedures known to those skilled in the art by use of a mercaptide.
  • Sodium mercaptide is preferred.
  • the alkali hydrolysis reaction is carried out with conventional procedures known to those skilled in the art.
  • the thiol ester optionally dissolved in a suitable solvent, for example a ketone, such as acetone, preferably a water-miscibile solvent, is treated with an aqueous alkali solution, for example 10% w/v potassium hydroxide.
  • a suitable solvent for example a ketone, such as acetone, preferably a water-miscibile solvent
  • an aqueous alkali solution for example 10% w/v potassium hydroxide.
  • the reaction temperature is uncritical, even though heating from room temperature to the reflux temperature would be preferable.
  • the reaction time can be determined depending on the reaction conditions, for example checking its progress.
  • the present invention also relates to a process for the preparation of ⁇ -arylpropionic acids, which comprises the transformation of the thiol ester of formula (V)
  • the resolution of the racemic mixtures into the enantiomers via formation of diastereomers is a well known, usually employed method.
  • the corresponding thiol esters can, through said route, provide the pharmaceutically interesting (S) enantiomers as well as the not active or less active (R) enantiomers, which can be subjected to racemization and recycled .
  • ketoprofen or
  • the present invention also relates to a process for the preparation of 4-isobutylbenzoic acid ester, which is a starting compound to obtain the thiol ester of formula (V) wherein Ar is 4-isobutylphenyl, and the resulting ⁇ -arylpropionic acid is 3-(4-isobutyl)- phenylpropionic acid or ibuprofen.
  • said ester is prepared by reaction of isobutylbenzene with oxalyl dichloride and subsequent treatment with methanol, or another suitable alcohol, to give the corresponding ester. Subsequently the thiol ester is obtained as described above.
  • S-alkyl ⁇ , ⁇ -dialkylthiopropanthioate for use in the Friedel-Crafts reaction, can be obtained reacting an alkyl acetate with tris(alkylthio)- methyllithium to give the trithioorthoester, and subsequent isomerization.
  • step 3 2,2,2-tris(methylthio)-1-(3-benzoyl)phenyl- ethanone was obtained by hydrolysis of the compound obtained in step 2) above (4.08 g, 10 mmol) with conc. HCl (2.04 g, 20 mmol) in ethyl ether (20 ml). The reaction is complete after 1 hour 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 substantially pure product is obtained in a 93% yield
  • the eluents used for the separation of the other intermediates are the following ones:
  • reaction mixture is poured into water and neutralized with concentrated hydrochloric acid, then extracted with ethyl ether.
  • the organic phase is washed with water (100 ml) and dried over sodium sulfate.
  • the crude residue resulting from the evaporation of the solvent under vacuum is chromatographed on a short silica gel column (eluent: petroleum ether/ethyl ether, 9.8:0.2). S-methyl 2-phenyl-2-(methylthio)thiopropionate is obtained (2.05 g, 91%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de préparation d'acides α-arylpropioniques, en particulier ceux présentant un intérêt sur le plan pharmaceutique, ce qui consiste à effectuer l'hydrolyse de l'ester thiol d'alkyle. Dans un autre mode de réalisation, ledit procédé permet également d'obtenir les énantiomères simples.
PCT/EP1997/001258 1996-03-15 1997-03-12 PROCEDE DE PREPARATION D'ACIDES α-ARYLPROPIONIQUES ET DE LEURS INTERMEDIAIRES WO1997034860A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20268/97A AU2026897A (en) 1996-03-15 1997-03-12 A process for the preparation of alpha-arylpropionic acids and the intermediates thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT96MI000500A IT1283251B1 (it) 1996-03-15 1996-03-15 Procedimento per la preparazione di acidi alfa-arilpropionici e relativi intermedi
ITMI96A000500 1996-03-15

Publications (1)

Publication Number Publication Date
WO1997034860A1 true WO1997034860A1 (fr) 1997-09-25

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PCT/EP1997/001258 WO1997034860A1 (fr) 1996-03-15 1997-03-12 PROCEDE DE PREPARATION D'ACIDES α-ARYLPROPIONIQUES ET DE LEURS INTERMEDIAIRES

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Country Link
AU (1) AU2026897A (fr)
IT (1) IT1283251B1 (fr)
WO (1) WO1997034860A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6201151B1 (en) * 1998-12-17 2001-03-13 National Science Council Of Republic Of China Processes for preparing optically active (S)-α-aryl propionic acid or ester therof
CN110396040A (zh) * 2019-09-09 2019-11-01 东南大学 一种一锅法合成二芳基甲缩酮的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5350137A (en) * 1976-10-20 1978-05-08 Sagami Chem Res Center Alpha-(p-isobutyllhenyl)propionic acid thiol ester

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5350137A (en) * 1976-10-20 1978-05-08 Sagami Chem Res Center Alpha-(p-isobutyllhenyl)propionic acid thiol ester

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
D. SEEBACH ET AL.: "S-Methyl thiocarboxylates from aldehydes and ketones through ketene thioacetals.", SYNTHESIS, July 1975 (1975-07-01), STUTTGART DE, pages 461 - 462, XP000674283 *
DATABASE WPI Section Ch Week 7824, Derwent World Patents Index; Class B05, AN 78-43077A, XP002034030 *
G.A. RUSSELL ET AL.: "Beta-keto sulfoxides.", JOURNAL OF ORGANIC CHEMISTRY, vol. 35, no. 3, March 1970 (1970-03-01), EASTON US, pages 764 - 770, XP000674279 *
M. BARBERO ET AL.: "Synthesis of trimethyl alpha-keto trithioorthoesters and dimethyl alpha-keto dithioacetals by reaction of esters with tris(methylthio)methyllithium", JOURNAL OF ORGANIC CHEMISTRY, vol. 60, no. 19, 22 September 1995 (1995-09-22), EASTON US, pages 6017 - 6024, XP000674298 *
M. BARBERO ET AL.: "Synthetic application of lithiated tris(methylthio)methane", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 7 September 1993 (1993-09-07), LETCHWORTH GB, pages 2075 - 2080, XP000674271 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6201151B1 (en) * 1998-12-17 2001-03-13 National Science Council Of Republic Of China Processes for preparing optically active (S)-α-aryl propionic acid or ester therof
CN110396040A (zh) * 2019-09-09 2019-11-01 东南大学 一种一锅法合成二芳基甲缩酮的方法
CN110396040B (zh) * 2019-09-09 2020-12-15 东南大学 一种一锅法合成二芳基甲缩酮的方法

Also Published As

Publication number Publication date
ITMI960500A0 (fr) 1996-03-15
IT1283251B1 (it) 1998-04-16
ITMI960500A1 (it) 1997-09-15
AU2026897A (en) 1997-10-10

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