Process for the preparation of thiazolidinedione derivatives

Details Process for the preparation of thiazolidinedione derivatives Process for the preparation of thiazolidinedione derivatives

2002-11-05

2003-09-16

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S060000

Reexamination Certificate

active

06620941

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with a novel process for the preparation of thiazolidinedione derivatives, especially with the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione and its salts. 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione and its salts are pharmaceutically active compounds. These compounds are known in the art and are described for example in International Patent Application WO 94/27995. They are especially useful for the prophylaxis and/or treatment of diabetes mellitus type I and II.
Methods for the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione have been described in WO 94/27995. However, these methods include a large number of individual reaction steps. Further, the methods known in the art exhibit a low yield, which makes them unsuitable for the commercial large scale production of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione.
It has surprisingly been found that using the process according to the present invention 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione can be prepared with less process steps under moderate conditions with an outstanding yield.
SUMMARY OF THE INVENTION
The present invention refers to a process for the preparation of compounds of formula I
comprising bromomethylation or chloromethylation of a compound of formula II
to obtain a compound of formula III
and subsequent reaction with a compound of formula IV
to yield said compounds of formula I,
wherein R
1
represents aryl or heteroaryl and X represents Cl or Br.
This process provides an efficient method for producing compounds of formula I. Compared to the processes known in the art, the process of the present invention exhibits a higher yield as well as a reduced number of reaction steps. Further, crude intermediate products can mostly be used in subsequent reaction steps without the need of any additional purification steps.
According to the present invention, terms “chloromethylation” and “bromomethylation” signify the introduction of a —CH
2
Cl or —CH
2
Br group respectively.
The term “mesylation” signifies the introduction of a methanesulfonyl group which can e.g. be performed by a reaction with methanesulfonylchloride.
The term “tosylation” signifies the introduction of a toluenesulfonyl group which can e.g. be performed by a reaction with toluenesulfonylchloride.
In this specification the term “lower” is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term “alkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms.
The term “lower alkyl” refers to a branched or straight chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, i-butyl, n-butyl, t-butyl and the like with methyl and ethyl being preferred.
The term “alkoxy” refers to the group alkyl-O—, the term “lower alkoxy” to the group lower-alkyl-O—.
The term “aryl” relates to the phenyl or naphthyl group which can optionally be mono-, di- or tri-substituted by alkyl, halogen, hydroxy, alkoxy, aryloxy, or aryl-alkoxy. Mono- and di-substituted phenyl or naphthyl groups are preferred.
The term “heteroaryl” refers to an aromatic 5- or 6-membered ring which can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thiophenyl, isoxazolyl, oxazolyl or imidazolyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term “aryl”.
The term “halogen” refers to fluorine, chlorine, and bromine, preferably to chlorine and bromine and more preferably to bromine.
The term “pharmaceutically acceptable salt” refers to conventionally known pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases. The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of Formula I and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.
In detail, the present invention refers to a process for the preparation of compounds of formula I
comprising bromomethylation or chloromethylation of a compound of formula II
to obtain a compound of formula III
and subsequent reaction with a compound of formula IV
to yield said compounds of formula I,
wherein R
1
represents aryl or heteroaryl and X represents Cl or Br.
In a preferred embodiment of the invention, a compound of formula II is bromomethylated. In a more preferred embodiment said bromomethylation is carried out in a solvent in the presence of HBr and formaldehyde.
Solvents for the above reaction are known to persons skilled in the art. Preferred solvents are aromatic solvents, e.g. toluene, halogenated hydrocarbons, e.g. CH
2
Cl
2
, esters, e.g. ethylacetate, ethers, e.g. dioxane, and mixtures thereof. A particularly preferred solvent is CH
2
Cl
2
.
Formaldehyde can be provided as formaline solution, trioxane or paraformaldehyde. Preferrably formaldehyde is provided as trioxane in said bromomethylation.
HBr can be provided as gas or as aqueous solution. Aqueous solutions are commercially available, e.g. at concentrations of 48% or 62%. The bromomethylation can e.g. be carried out with aqueous HBr of a concentration between 30% and 69%. An aqueous solution with a HBr concentration in the range between 45% and 62% is preferred.
The bromomethylation can be carried out in a wide range of temperatures, e.g. from −20 to +40° C. Preferably, the bromomethylation is carried out at a temperature between −10 and +10° C. The atmospheric pressure during the reaction is not critical.
The reaction of a compound of formula III with a compound of formula IV may proceed by the formation of a salt of a compound of formula IV, e.g. a di-sodium salt, a di-potassium salt or a di-lithium salt, followed by reaction of that salt with the compound of formula III. A di-potassium salt of a compound of formula IV can be prepared by methods known in the art, e.g. by reacting a compound of formula IV with potassium amide in liquid ammonia or with potassium tert.-butoxyde in THF. Methods for preparing a di-sodium salt of a compound of formula IV are also known in the art, e.g. by reacting a compound of formula IV with sodium amide in liquid ammonia or with sodium tert.-butoxyde in THF.
A further preferred embodiment relates to a process as described before, wherein said reaction of a compound of formula III with a compound of formula IV comprises the formation of a di-lithium salt of a compound of formula IV. Said di-lithium salt can e.g. be obtained by reacting a compound of formula IV with lithium diisopropylamide in THF.
Preferably R
1
represents phenyl. In another preferred embodiment R
1
represents thiophen-2-yl.
If desired, compounds of formula I can be converted to a corresponding salt, preferably a pharmaceutically acceptable salt, most preferably the sodium salt. Such a co

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