WO1997043283A1 - New process for preparing troglitazone - Google Patents

Abstract

In a cost-effective process for preparing troglitazone (I), a compound of general formula (III) is used.

Description

New process for the production of troglitazone

The present invention relates to a new process for the preparation of troglitazones, the compound of the formula (I)

The compound of formula (I) is described in EP-139421 and known under the name TROGLITAZONE as an antidiabetic agent for the oral treatment of diabetes mellitus, especially in the case of type II or type IIb. But also in type I, the substance proves to be effective because according to more recent knowledge, it lowers the need for exogenous insulin. It also has a positive influence on elevated blood pressure values and brings about a reduction in the levels of Tπglyceπd and cholesterol. It is therefore also suitable for the prophylaxis of atherosclerotic diseases. The substance is therefore a valuable substance Medicines for the treatment of diabetic metabolic diseases, the effectiveness of which has been demonstrated in numerous clinical studies

Patent EP-139421 describes a production process for the compound (I), according to which the compound of the formula (VIII)

mit einem Fluornitrobenzol umsetzt und die erhaltene Nitroverbindung der Formel (IX)ORIGINAL DOCUMENTS

reacted with a fluoronitrobenzene and the nitro compound of the formula (IX) obtained

converted into the desired compound (I) in 6 further stages

For the production of quantities on a multi-kg scale, this described method has some disadvantages with regard to safety, upscaling, handling and synthetic effort. Among other things, the reaction of the compound of the formula (XII)

for the compound of the formula (XIII)

diazotiert und mit giftigem Acrylsaureester umgesetzt werden, wobei diese Reaktion mit unbefriedigenden Ausbeuten verlauft Ausserdem ist die Übertra¬ gung dieser Reaktion in einen grosseren Maßstab aus Sicherheitsgründen äußerst problematisch Die verwendete MOM-Schutzgruppe wird zudem über eine Kondensation mit Chlormethyl-methylether eingeführt Dieser Chlor- methylether ist als eindeutig krebserregend eingestuft und erfordert daher beim Umgang besondere Schutz- und Uberwachungsmaßnahmen

be diazotized and reacted with toxic acrylic acid ester, this reaction proceeding with unsatisfactory yields. In addition, the transfer of this reaction to a larger scale is extremely problematic for safety reasons. The MOM protective group used is also introduced via condensation with chloromethyl methyl ether. This chloromethyl ether is classified as clearly carcinogenic and therefore requires special protective and monitoring measures when handling

Despite the disadvantages described, the above-mentioned reaction sequence has hitherto been necessary for the preparation of the compound (I) because no other economically suitable method for the alkylation of phenolic OH groups with sterically hindered alkyl groups which differ from the alcohols of the general formula ( II)

was known (e.g. Takao Yoshioka et al J Med Chem, volume 32, page 421 [1989], from Beilstein's handbook of organic chemistry, Springer Verlag, Berlin 1982, and from the database 'BS 9503', Beilstein chemical data and software GmbH, 1995) The patent application EP-454501 describes the alkylation of p-hydroxybenzaldehyde with a similar type of compound. The activating group used is iodine, which is produced via the mesylate step. This reaction via the mesylate is uneconomical. since it gives poorer yields and has to be carried out at higher temperatures The object of the invention is to be seen to provide a process for the production of troglitazones which enables economical synthesis.

It was surprisingly found that phenols and their derivatives, in particular 4-hydroxybenzaldehyde, can be alkylated with compounds of the general formula (II) under mild conditions and in high yield and purity by first converting them into the corresponding tnfluoromethylsulfonates of the general formula (III )

transferred and reacted with the appropriately substituted phenols

Within the framework of this alternative synthesis, the problem was also solved that, when the thiazolidinedione was built up by condensing the unsubstituted thiazolidinedione with an aryl aldehyde, as it must be attached to the above-mentioned alkylation, the catalytic hydrogenation of the double bond in the arylene compounds of the general formula ( V),

as described, for example, in EP-454501, only leads to unsatisfactory results, since the catalyst is deactivated by the sulfur in the thiazole din and a quantitative implementation in an economically reasonable time and with economic use of the catalyst is not possible

It has now also been found that the compounds of the general formula (V) according to the known electron transfer technique by Watt et al (J Org Chem, Volume 40, S 127 [1975]) with magnesium or activated aluminum in methanol, dioxane or tetrahydrofuran in high yields and under economically advantageous conditions to give the compounds of the general formula (VI)

can be reduced

It has surprisingly proven to be advantageous to use strong acids, for example molten pyridine hydrochloride, to split off the protective group R ₄

The process according to the invention thus consists of a reaction sequence, which is characterized in that one first starts from a compound of the general formula (II)

in der R4 eine reduktiv stabile Schutzgruppe für phenolisches OH bedeutet. Solche Schutzgruppen sind beispielsweise aus der Biotechnologie bekannt, z. B. Benzyl oder MOM, bevorzugt ist Benzyl. Verbindungen der allgemeinen Formel II werden mit einem Trifluormethansulfonylierungsmittel, bevorzugt Trifiuormethansulfonsäure-anhydrid oder Trifluormethylsulfonylchlorid zu einer Verbindung der allgemeinen Formel (III) umgesetzt

in which R4 is a reductively stable protective group for phenolic OH. Such protective groups are known for example from biotechnology, e.g. As benzyl or MOM, benzyl is preferred. Compounds of the general formula II are reacted with a trifluoromethanesulfonylating agent, preferably trifluoromethanesulfonic acid anhydride or trifluoromethylsulfonyl chloride, to give a compound of the general formula (III)

and the triflate obtained is preferably alkylated without further purification with 4-hydroxybenzaldehyde to give a compound of the general formula (IV).

The compounds of the general formula (IV) are then condensed with thiazolidinedione in a manner known per se to give compounds of the general formula (V)

(V)

und diese durch Reduktion der Doppelbindung vorzugsweise mit einem Alkali- oder Erdalkalimetall oder aktiviertem Aluminium in einem protischen Losungsmittel, insbesondere mit Magnesium oder aktiviertem Aluminium in Methanol, Dioxan oder Tetrahydrofuran unter Zusatz geringer Mengen Wasser zu einer Verbindung der allgemeinen Formel (VI) reduziert

and this is reduced by reducing the double bond, preferably with an alkali or alkaline earth metal or activated aluminum in a protic solvent, in particular with magnesium or activated aluminum in methanol, dioxane or tetrahydrofuran with the addition of small amounts of water to a compound of the general formula (VI)

The compounds of the general formula (VI) are converted into the desired compound of the formula (I) in good yields by treatment with strong acids, for example with molten pyridohydrochloride or, in the case of R4 = benzyl, optionally by hydrogenation with catalytic hydrogen with elimination of the protective group R4. convicted

As a result, 2 steps less are required for the preparation of the compound (I) than according to the previously used method from EP 139 421. In addition, the high overall yield of 40% offers a further, additional advantage in comparison to the known method from EP 139 421, which only delivers an overall yield of 24.6%. Therefore, the new production process represents a significant advance over the prior art

The main advantage of the process according to the invention consists in the process step of the gentle reduction of compounds of the general formula (V) with magnesium or preferably activated aluminum to compounds of the general formula (VI), which is easy to carry out in high yields, by using the mild reducing agents, in particular when used of aluminum, can reduce sensitivity Protective groups R ₄ are used and the contamination of the compounds (VI) by partial gradual reductions in the aromatic ring systems, such as those which take place, for example, in the long-term catalytic hydrogenations, are largely prevented

The reaction can also be carried out in aprotic, polar solvents which are miscible with small amounts of water, such as dioxane or tetrahydrofuran, with the addition of small amounts of water as a proton donor. This variant is a particularly gentle method of reduction. The reaction is carried out at room temperature or elevated temperature preferably carried out at 40 ° C. The activation of the aluminum is preferably carried out by treatment with a dilute mercury salt solution

The following examples are intended to explain the new method for preparing the compound of the formula (I). The solvents, reaction conditions, catalysts and reactants used illustrate the invention only by way of example and can be varied in a known manner

example 1

6-benzyloxy-2-hvdroxymethyl-2 5 7 8-tetramethyl-chroman

A solution of 940 g (3.98 mol) of 6-hydroxy-2-hydroxymethyl-2 5 7 8-tetramethyl-chroman in 3 5 liters of DMF is added in portions with 96 g of 95 percent sodium hydride while stirring with ice cooling under a nitrogen atmosphere. Then the mixture is stirred 1 h after and with renewed ice cooling, a solution of 460 ml (4 mol) of benzyl chloride in 2 0 liters of toluene is then removed from the ice bath and the mixture is stirred overnight. The mixture is poured onto 5 kg of ice, extracted three times with 1 5 liters of ethyl acetate , dries the extracts and evaporates them. The residue is suspended with 200 ml of ethyl acetate, 4 liters of isohexane are added and the mixture is stirred for 4 hours at room temperature. The precipitate is filtered off with suction, washed with isohexane and dried at 40 ° C. in vacuo 1167 g (90%) 6-benzyloxy-2 5 7 8-tetra-methyl-2- (tπfluormethylsulfonyl-oxymethyl) -chroman, mp 73-74 ° C.

Example 2

^β- Benzyloxy-2 5 7 8-tetramethyl-2- (trιfluormethylsulfonyloxymethyl) -chroman

To a solution of 326 4 g (1 0 mol) of 6-benzyloxy-2-hydroxymethyl-2 5 7 8-tetramethyl-chroman in 1 6 liters of anhydrous pyridine are added 164 1 ml (1 0 mol) of fluorofluoromethanesulfonic anhydride with stirring and ice cooling drips and stirred for 1 h under ice cooling. Then pour onto 1 5 kg of ice, acidify to pH 3 with dilute hydrochloric acid and extract twice with 1 5 liters of ethyl acetate. The extracts are dried and evaporated. The residue is triturated with 2 liters of isohexane and the crystals become suction filtered. 320 1 g (70% of theory) of 6-benzyloxy-2 5 7 8-tetramethyl-2- (tπfluoromethylsulfonyloxy) -chroman are obtained, mp 89-90 ° C. Example 3

4- (6-Benzyloxy-2 5 7 8-tetramethyl-chroman-2-ylmetvhloxy) benzaldehvd

A solution of 91 7 g (0 2 mol) of 6-benzyloxy-2 5 7 8-tetramethyl-2- (tπfluoromethylsulfonyl-oxy) -chroman and 244 g (0 2 mol) of 4-hydroxybenzaldehyde in 200 ml of dimethylformamide is used 54 g potassium carbonate were added and the mixture was stirred overnight at room temperature. Then poured onto 1 kg ice, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were dried and evaporated. Yield 83 5 g (97%), colorless oil

Example 4

5- {4- (6-Benzyloxy-2 5 7 8-tetramethyl-chroman-2-ylmethoxy) -benzylιden> -2 4- thiazohdindione

A mixture of 121 g (0 2 mol) of 4- (6-benzyloxy-2 5 7 8-tetramethyl-chroman-2-ylmetyhioxy) benzaldehyde, 39 5 g (0 34 mol) of 2 4-thιazolιdιndιon and 86 1 g ( 1 05 mol) of anhydrous sodium acetate is melted at an outside temperature of 150 ° C. and left at this temperature for 2 hours. After cooling, 500 ml of water are added and the mixture is extracted twice with 1 liter of ethyl acetate. The extracts are dried and evaporated. The residue is taken up with 200 ml Boiled methanol, cooled to 0 ° C and suction filtered. The precipitate is dried in a forced-air drying cabinet at 50 ° C. 136 g (91%) of 5- {4- (6-benzyloxy-2 5 7 8-tetramethy! -Chroman-2- ylmethoxy) -ben- zylιden} -2 4-thιazolιdιndιon, mp 145-147 ° C. Example 5

544- (6-Benzyloxy-2 5 7 8-tetramethyl-chroman-2-ylmethoxy) benzyl) -2 4-thiazohdinedione

A solution of 119 g (0 22 mol) of 5- {4- (6-benzyloxy-2 5 7 8-tetramethyl-chroman-2-ylmethoxy) -benzyhden} -2.4-thιazohdιndιon in a mixture of 1 liter of tetrahydro-furan and 1 liter of methanol is mixed with 53 5 g (2 2 mol) of magnesium chips at room temperature and the start of the reaction is initiated by adding a few iodine crystals. The mixture is stirred for a further 2 hours at 35 ° C. and then heated in an oil bath for 1 hour to reflux the residue is evaporated with 500 ml of water, acidified and extracted twice with 300 ml of ethyl acetate. The extracts are dried and evaporated. The residue is suspended in 500 ml of water, stirred for 2 hours and the precipitate is filtered off with suction. The precipitate is mixed 1 part of isohexane and 1 part of ethyl acetate were dissolved and filtered with this mixture as eluans over a short column of silica gel (control of the eluate using a thin layer chromatogram). The eluate is evaporated and the residue after streaking through n dried at 50 ° C in a circulating air dryer. 99 6 g (83%) of 5- {4- (6-benzyloxy-2 5 7 8-tetramethyl-chroman-2-yl-methoxy) -benzyl} -2 4-thιazohdιndιon are obtained , Mp 97-100 ° C

Example 6

5- {4- (6-Hvdroxy-2 5 7 8-tetramethyl-chroman-2-ylmethoxy) benzyl) -2 4-thiazolidinedione

A mixture of 53 g (0 1 mol) of 5- {4- (6-benzyloxy-2 5 7 8-tetra-methyl-chroman-2-ylmethoxy) -benzyl} -2 4-thιazolιdιndιon and 265 g of Pyπdin- hydrochloπd 60 min at 150 ° C to a homogeneous melt after cooling it is taken up in 100 ml of water and made acidic with 50 ml of 2N hydrochloric acid, then extracted three times with 100 ml of ethyl acetate, dried, evaporated and crystallized from a mixture of acetone and isohexane to yield 38 4 g (87%) 5 - {4- (6-Hydroxy-2.5.7 8-tetra-methyl-chroman-2-ylmethoxy) -benzyl} -2 4-thιazolιdιndιon, mp 183-186 ° C

The total yield of (I), based on (II) used, R ₄ = H, is thus 40% by the process according to the invention

Claims

claims 1. Process for the preparation of troglitazones of the formula

characterized in that a compound of general formula II

in which R _{4 is} a customary protective group for phenolic OH, is converted into a compound of the general formula III,

reacting this compound with p-hydroxybenzaldehyde to give a compound of the formula IV,

this with 2,4-thιazolιdιndιon to a compound of general formula V,

implements

is reduced and then the protective group R _{4 is} split off 2 The method of claim 1, wherein R _{4 is} a benzyl radical A method according to claim 1 or 2, wherein the triflate derivative III is prepared by reacting with tπfluoromethanesulfonic acid anhydride or trifluoromethylsulfonyl chloride 4. The method according to any one of claims 1-3, characterized in that the compound III is reacted to the compound IV without further purification. 5 The method according to any one of claims 1-4, characterized in that the reduction of the double bond in the compound of the general formula V is carried out with alkali or alkaline earth metal. 6 The method according to claim 5, characterized in that the reduction is carried out with magnesium. 7 The method according to any one of claims 1 -5, characterized in that the protective group R _{4 is} split off in molten pyridine hydrochloride 8 Process for the gentle reduction of compounds of the formula (V), magnesium or activated aluminum being used as the reducing agent in polar, aprotic or protic solvents such as methanol, dioxane or tetrahydrofuran with the addition of small amounts of water