Methods for the preparation of 4-hydroxybenzothiophene

Details Methods for the preparation of 4-hydroxybenzothiophene Methods for the preparation of 4-hydroxybenzothiophene

2000-07-26

2001-09-18

Tsang, Cecilia (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06291685

ABSTRACT:

BACKGROUND OF THE INVENTION
Methods for the preparation of 4-hydroxybenzothiophene have been described by Iwasaki et al. (1991) J. Org. Chem. 1991. 5, 1922. Here a cyclocarbonylation of a primary allylacetate is performed in presence of a high catalyst loading. Further, this process is characterized by at least five process steps which in part require extreme reaction conditions. Therefore, a simpler more efficient process utilizing less process steps has been long desired.
SUMMARY OF INVENTION
The present invention is concerned with a novel process for the preparation of benzothiophene derivatives, especially with the preparation of 4-hydroxybenzothiophene. 4-Hydroxybenzothiophene is a building block for pharmaceutically active compounds, e.g. 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxyl]-7-benzothiophenylmethyl]-2,4-thiazolidinedione. This compound is known in the art and is described for example in International Patent Application WO 94/27995. It is especially useful for prophylaxis and treatment of diabetes mellitus type I and II.
Surprisingly it has been found that using the process according to the present invention 4-hydroxybenzothiophene can be prepared with less process steps under moderate conditions with an outstanding yield.
DETAILED DESCRIPTION
In accordance with this invention, a new procedure is provided for preparing 4-hydroxybenzothiophene having the formula
from a compound of
wherein Y is halogen or —OR; and
—OR is an aryloxy group or a group of formulae —O—(CO)—R′, —O—(CO)—O—R″, or —O—(PO)—(OR″)
2
, wherein R′ is alkyl, perfluoro-C
1-20
-alkyl, aryl, R″ is alkyl, aryl or benzyl;
which comprises cyclocarbonylating the compound of formula II by reacting, in an organic solvent medium containing a carboxylic acid anhydride and a base, the compound of formula II with carbon monoxide in the presence of a carbonylation catalyst capable of complexing with carbon monoxide to produce the carboxylic acid ester of the compound of formula I as a reaction product and thereafter saponifying this reaction product to produce the compound of formula I above.
The cyclocarbonylation is carried out by introducing carbon monoxide into the reaction medium containing the compound of formula II above and a carbonylation catalyst capable of complexing with carbon monoxide to produce the carboxylic acid ester of the compound of formula I as a reaction product. The saponification step is carried out after this reaction product is formed. The saponification is carried out by adding a base to the reaction medium so that the pH is raised to any value of from 8 to 14.
Surprisingly, it has been found that using the process of this invention, the 4-hydroxybenzothiophene can be prepared with less process steps under moderate conditions and with an outstanding yield. The process also provides an efficient cyclocarbonylation reaction under mild conditions in a single reaction medium so that the starting material for this reaction, ie., the compound of formula II, does not have to be purified such as by distillation but can be used as crude material. Therefore, this process provides an efficient cyclocarbonylation reaction under mild conditions. In addition, substrates for the cyclocarbonylation reaction (compound of Formula II) do not need to be purified, e.g. by distillation, but can be used as “crude” material.
According to the present invention, the term “cyclocarbonylation” refers to an introduction of a carbonyl group by means of carbon monoxide gas coupled with the formation of a cyclic ring structure.
The term “saponification” refers to the hydrolysis of an ester under basic conditions.
The term “transition metal compound” refers to a metal-phosphine complex compound wherein the term metal refers to Pd, Pt, Ru, Co, Rh or Ni, preferably Pd.
The term “ligand” refers to phosphine, arsine or stibine derivatives, preferable phosphine derivatives, of general formulae P(R
1
)(R
2
)(R
3
), (R
1
)(R
2
)P—(X)—P(R
1
)(R
2
), As(R
1
)(R
2
)(R
3
) or Sb(R
1
)(R
2
)(R
3
), preferably P(R
1
)(R
2
)(R
3
), wherein R
1
, R
2
, and R
3
are below.
The term “alkyl” refers to a branched or straight chain monovalent alkyl radical of one to nine carbon atoms (unless otherwise indicated), preferably one to four (lower) 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.
The term “aryl” refers to a monovalent carbocyclic aromatic radical, e.g. phenyl, optionally substituted, independently, with halogen, lower-alkyl, lower-alkoxy, lower-alkylenedioxy, carboxy, trifluoromethyl and the like, with phenyl being especially preferred.
The term “lower alkanoic acid” refers to those lower alkanoic acids containing from 2 to 6 carbon acids such as propionic acid, acetic acid, etc.
The term “aryloxy”, signifies a group of the formula aryl-O— in which the term “aryl” has the significance given above. Phenyloxy is a preferred example of such an aryloxy group.
The term “alkoxy”, alone or in combination, signifies a group of the formula alkyl-O— in which the term “alkyl” has the significance given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.
The term “alkylenedioxy” refers to C
1-3
-alkyl-dioxy groups, such as methylenedioxy, ethylenedioxy or propylenedioxy.
The term “halogen” refers to fluorine, chlorine, and bromine.
In more detail, the present invention refers to a process for the preparation of compounds of formula I
comprising cyclocarbonylation of a compound of formula II
wherein Y is halogen or —OR;
—OR is an aryloxy group or a group of formulae —O—(CO)—R′, —O—(CO)—O—R″ or —O— (PO)—(OR″)
2
, wherein R′ is alkyl, perfluoro-C
1-20
-alkyl, aryl, R″
0
is alkyl, aryl or benzyl;
followed by saponification.
In a preferred embodiment of the invention, the cyclocarbonylation reaction is carried out in the presence of a base and the carbonylation catalyst is a complex of a transition metal compound with a ligand.
In a preferred embodiment of this invention, the cyclocarbonylation reaction carried out in the presence of a base and a carboxylic acid anhydride, one utilizes a catalyst which is a transition metal compound complexed with a ligand. Cyclocarbonylation reactions and their conditions are known. Any of the conventional conditions utilized in such cyclocarbonylation reactions can be utilized in accordance with the process of this invention.
In accordance with the process of this invention, this cyclocarbonylation reaction is carried out in the presence of a carbonylation catalyst capable of complexing with carbon monoxide. Any conventional carbonylation catalyst capable of complexing with carbon monoxide can be utilized in accordance with this invention. Among the preferred catalysts are those catalysts which are transition metal compounds complexed with a ligand. Transition metal compounds useful for the process of the present invention comprise salts of Pd, Pt, Ru, Co, Rh— or Ni and also include transition metals on an inert support such as Pd/C. The use of transition metal compounds as catalysts has been described for example in Matsuzaka et al. (1988) J. Org. Chem. 53, 3832. Preferred transition metal compounds are salts of palladium, e.g. Pd(OAc)
2
, Pd
2
dba
3
, PdCl
2
, Pd
2
Cl
2
(&pgr;-allyl)
2
, PdCl
2
(NCMe)
2
, [Pd(NCMe)
4
] (BF
4
)
2
, and most preferably Pd(OAc)
2
. The mentioned catalysts are known in the art (e.g. U.S. Pat. No. 5,380,861; “Carbonylation, Direct Synthesis of Carbonyl Compounds”, H. M. Colquhoun, D. J. Thompson, M. V. Trigg, Plenum Press, 1991) and/or are commercially available (e.g. from Fluka, Buchs, Switzerland or Strem Chemicals, Kehl, Germany).
The ligand of the transition metal compound in the catalyst may be selected from a group consisting of phosphine, arsine or stibine derivatives, preferable phosphine derivatives of general formulae P(R
1
)(R
2
)(R
3
), (R
1
)(R
2
)P—(X)—P(R
1
)(R
2
), As(R
1
)(R
2
)(R
3
) or

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