Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-18
2001-03-27
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S410000, C562S432000, C568S074000, C568S075000
Reexamination Certificate
active
06207837
ABSTRACT:
TECHNICAL FIELD
This invention relates to a process for producing diaryl sulfide derivatives or salts thereof which are intermediates of pharmaceutical compounds. The invention also relates to a process for producing dibenzo[b,f]thiepine derivatives using such intermediates.
BACKGROUND ART
Symmetric and asymmetric diaryl sulfide derivatives are compounds useful as intermediates in the production of many pharmaceutical compounds. For example, bis(3,5-dimethoxy-phenyl)disulfide which is a symmetric diaryl sulfide derivative is a compound useful as an intermediate for the synthesis of dibenzo[b,f]thiepine derivatives. Methods of synthesizing dibenzo[b,f]thiepine derivatives from bis(3,5-dimethoxyphenyl)disulfide have already been described in Japanese Patent Application No. 7904/1996 (International Publication WO97/25985) and so forth.
Compounds bearing a dibenzo[b,f]thiepine skeleton are known to include compounds having a broad range of pharmacological activities such as an anti-inflammatory action [Chemical and Pharmaceutical Bulletin 36, 3462 (1988)], an antispasmodic action (Japanese Patent Public Disclosure No. 160288/1975), an antiestrogenic action [Journal of Medicinal Chemistry 26, 1131 (1983)], an antioxidative action (International Patent Application No. 96/10021), a cerebral function improving action (International Patent Application No. 96/25927), and a trachea dilating action (Japanese Patent Application No. 7904/1996, or International Publication WO97/25985). For effective utilization of these pharmacological activities, a method capable of efficient massive supply of compounds having the dibenzo[b,f]thiepine skeleton is desired.
DISCLOSURE OF INVENTION
The present invention purports to realize efficient synthesis of diaryl sulfide derivatives useful as intermediates of pharmaceutical compounds and to provide a convenient process for producing large volumes of dibenzo[b,f]thiepine derivatives using such intermediates.
In order to realize massive and convenient production of dibenzo[b,f]thiepine derivatives, the present inventors conducted various experiments on various starting materials, reactions and intermediates and found that thiol derivatives, among other things, reacted with halogen-substituted phenyl derivatives via the intermediate disulfide derivatives to produce diaryl sulfide derivatives. Based on these findings, the inventors continued the intensive research and finally accomplished the present invention, which relates to a process for producing diaryl sulfide derivatives or salts thereof comprising reacting halogen-substituted phenyl derivatives with disulfide derivatives in the presence of metal catalysts to produce symmetric or asymmetric diaryl sulfide derivatives, as well as a process for producing dibenzo[b,f]thiepine derivatives by known techniques using said symmetric or asymmetric diaryl sulfide derivatives.
Thus, the present invention in essence relates to a process for producing diaryl sulfide derivatives or salts thereof by reacting halogen-substituted phenyl derivatives of the general formula (1):
(where X is a halogen atom and R
1
-R
5
is any substituent selected from among hydrogen, a lower alkyl group, a lower cycloalkyl group, an aryl group, a halogen atom, a lower alkoxyl group, an amino group, an N-lower acylamino group, a nitro group, a lower alkylthio group and a carboxyl group) with disulfide derivatives of the general formula (2):
(where R
6
-R
10
is any substituent selected from among hydrogen, a lower alkyl group, a lower cycloalkyl group, an aryl group, a halogen atom, a lower alkoxyl group, an amino group, an N-lower acylamino group, a nitro group, a lower alkylthio group and a carboxyl group) in the presence of metal catalysts to form a sulfide bond, thereby producing diaryl sulfide derivatives of the general formula (3):
(where R
1
-R
10
are the same as defined above). The end compound diaryl sulfide derivatives or salts thereof are intermediates of pharmaceutical compounds, preferably dibenzo[b,f]thiepine derivatives. The salts of the general formula (3) include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and organic amine addition salts such as ammonium salt, triethylamine and piperidine.
The disulfide derivatives of the general formula (2) to be used in the invention are preferably compounds that are produced by oxidizing thiol derivatives of the general formula (4) as a starting material:
(where R
6
-R
10
is any substituent selected from among hydrogen, a lower alkyl group, a lower cycloalkyl group, an aryl group, a halogen atom, a lower alkoxyl group, an amino group, an N-lower acylamino group, a nitro group, a lower alkylthio group and a carboxyl group). The disulfide derivatives of the general formula (2) to be used in the invention may also be intermediates that are produced within the reaction system starting from the thiol derivatives of the general formula (4).
The present invention preferably relates to a process by which the desired diaryl sulfide derivatives or salts thereof are produced as intermediates for pharmaceutical compounds such as dibenzo[b,f]thiepine derivatives. The present invention adopts known techniques for converting the intermediate diaryl sulfide derivatives or salts thereof into pharmaceutical compounds such as dibenzo[b,f]thiepine derivatives. Preferred examples of the dibenzo[b,f]thiepine derivatives include 7,9-dimethoxy-10,11-dihydrodibenzo[b,f]thiepin-10-one of the formula (5):
7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one of the formula (6):
and 10,11-dihydrodibenzo[b,f]thiepin-1,3-diol of the formula (7):
The present invention also relates in essence to a process comprising the steps of reacting halogen-substituted phenyl derivatives with disulfide derivatives in the presence of metal catalysts to produce diaryl sulfide derivatives and applying known techniques to the obtained diaryl sulfide derivatives to produce the above-listed dibenzo[b,f]thiepine derivatives. More specifically, the invention relates in essence to a process for producing diaryl sulfide derivatives or salts thereof by the steps of:
reacting a 2-halobenzoic acid of the general formula (8):
(where X is a halogen atom) with bis(3,5-dimethoxyphenyl)-disulfide of the formula (9):
in the presence of a metal catalyst to form a sulfide bond, thereby producing 2-(3,5-dimethoxyphenylthio)benzoic acid of the formula (10):
then reducing the compound (10) to form an alcohol derivative of the formula (11):
reacting the compound (11) with a halogenating agent or a pseudo-halogenating agent to produce a halogen derivative of the general formula (12):
(where X is a halogen atom or a pseudo-halogen leaving group);
reacting the compound (12) with a nitrile forming agent to produce a nitrile derivative, or 2-(3,5-dimethoxyphenyl-thio)benzylnitrile of the formula (13):
hydrolyzing the compound (13) to generate a carboxylic acid derivative; and cyclizing this derivative by an intramolecular Friedel-Crafts reaction to yield 7,9-dimethoxy-10,11-dihydrodibenzo-[b,f]thiepin-10-one of the formula (5):
The invention further relates in essence to a process for producing diaryl sulfide derivatives or salts thereof in which the cyclized 7,9-dimethoxy-10,11-dihydrodibenzo[b,f]thiepin-10-one of the formula (5) is deprotected to yield a diol form, or 7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one of the formula (6):
The invention further relates in essence to a process for producing diaryl sulfide derivatives or salts thereof in which 7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one which is the diol compound of the formula (6) or 7,9-dimethoxy-10,11-dihydrodibenzo[b,f]thiepin-10-one which is the dimethoxy compound of the formula (5) is reduced and deprotect
Jinno Shuji
Ohtsuka Naomi
Okita Taka-aki
Lambkin Deborah C.
Nippon Suisan Kaisha Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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