Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1999-01-25
2000-02-01
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
568433, 549 49, 549 51, 549 57, C07C 4752, C07C 4500, C07D33352, C07D33356
Patent
active
060205318
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel production process of a benzothiophene compound which is a useful intermediate for synthesizing some kind of a 2-substituted-3-(4-substituted benzoyl)-6-hydroxybenzo-[b]thiophene derivative having an antiestrogenic activity, and an intermediate compound useful in the production process.
DESCRIPTION OF THE RELATED ART
Disclosed as a 2-substituted-3-(4-substituted benzoyl)-6-hydroxybenzo[b]thiophene derivative having an antiestrogenic activity in a W093/10113 pamphlet (=U.S. Pat. No. 5472962, EP-A-641791) is a group of compounds represented by the following formula (A): ##STR3## wherein: R represents a hydrogen atom, a hydroxy group, a lower alkoxy group, an acyloxy group or an N,N-di-lower alkyl substituted or unsubstituted carbamoyloxy group, group or cycloalkenyl group which may optionally be substituted with a lower alkyl group, a hydroxy group, an acyloxy group or an oxo group, represent a heterocyclic group which may further contain a hetero atom selected from O, S and N together with a nitrogen atom to which they are bonded,
It is disclosed in the WO pamphlet described above that a benzothiophene compound represented by the following formula: ##STR4## wherein R.sup.1 represents a lower alkyl group, and R.sup.2 represents a halogen atom; a lower alkyl group; or a cycloalkyl group or cycloalkenyl group which may optionally be substituted with a lower alkyl group, a hydroxy group, an acyloxy group or an oxo group, formula (A) described above. In the above WO pamphlet, the compound represented by the formula (I) described above is synthesized according to the following reaction formula 1 with 6-alkoxybenzo[b]-thiophene (a compound represented by the following formula (B)) being used as a starting material: ##STR5##
In the respective formulae described above, R.sup.a and R.sup.b each represent a lower alkyl group or represent a cycloalkyl group which may optionally be substituted with a lower alkyl group or an oxo group, together with a carbon atom to which they are bonded, and R.sup.1 and R.sup.2 have the same meanings as described above.
On the other hand, nothing on a synthetic process of the compound represented by the formula (B) described above which is a starting material in the reaction formula 1 described above is described in the above WO pamphlet. However, a process shown by the following reaction formula 2 described in J. Med. Chem., vol. 32, pp. 2548 to 2554 (1989) is known as a process for synthesizing the compound represented by the formula (B) described above in which R.sup.1 represents, for example, methoxy, that is, a compound represented by the following formula (B-1): ##STR6##
However, the yield of a ring-closing reaction in the reaction formula 2 described above is about 60%, and the regioselectivity is about 10:1. In addition, in a reaction (reaction in the reaction formula 1 described above) for introducing a substituent into the 2 position of the benzothiophene, butyl lithium which is not industrial is used as a reaction reagent, and it can never be said that a hydrogenation reaction following it is an industrially advantageous reaction.
The present inventors have continued various researches on a production process of the benzothiophene compound represented by the formula (I) described above, and as a result thereof, they have found a production process in which the benzothiophene compound represented by the formula (I) can be produced only at two steps with 3-alkoxythiophenol being used as a starting material using industrially advantageous reaction reagent and reaction conditions and which is excellent in a yield and a regioselectivity.
DISCLOSURE OF THE INVENTION
According to the present invention, provided is a production process of the benzothiophene compound represented by the formula: ##STR7## wherein R.sup.1 and R.sup.2 have the same meanings as described above, characterized by that a compound represented by a formula: ##STR8## wherein R.sup.1 and R.sup.2 have the same meanings as described above, is su
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Doguchi Koji
Sato Shuichiro
Shiraiwa Masafumi
Lambkin Deborah C.
Teikoku Hormone Mfg. Co. Ltd.
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