Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1996-02-23
1996-12-17
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540546, 540487, C07D49822
Patent
active
055854885
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an industrial process for selectively and efficiently producing indolocarbazole derivatives which have protein kinase C-inhibiting activity.
BACKGROUND ART
##STR2## In the formulae, R.sup.4 represents lower alkyl.
Hereinafter, compounds represented by Formula (I), Formula (II), Formula (III), and Formula (IV) are referred to as Compound (I), Compound (II), Compound (III), and Compound (IV), respectively. The same applies to the compounds of other formula numbers.
It is known that Compound (II) has protein kinase C-inhibiting activity, and the process for producing Compound (II) as shown above is disclosed in Japanese Published Unexamined Patent Application No. 155284/87. According to the process, Compound (II) is directly produced from Compound (I). However, in the process, Compound (III) wherein a nitrogen atom in the amide group is lower-alkylated, and Compound (IV) wherein both of a hydroxyl group and a nitrogen atom in the amide group are lower-alkylated are produced in large quantities as by-products at the same time. Thus, the yield of the desired Compound (II) is low, and a complicated technique unsuitable for mass production, such as silica gel chromatography, is required for purification.
DISCLOSURE OF THE INVENTION
The present invention relates to a process for producing an indolocarbazole derivative represented by Formula (II), comprising: selective silylation of a nitrogen atom in the amide group of Compound (I) for obtaining a compound represented by Formula (V): ##STR3## wherein R.sup.1, R.sup.2, and R.sup.3 independently represent lower alkyl or aryl; lower-alkylation of Compound (V) to obtain a silylated indolocarbazole derivative represented by Formula (VI): ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 have the same meanings as defined above; and the acidic treatment of the silylated indolocarbazole derivative.
In addition, the present invention provides a silylated indolocarbazole derivative represented by Formula (VI).
In the definitions of the groups in Formula (I) to Formula (VI), the lower alkyl means a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl pentyl, isopentyl, neopentyl, and hexyl. The aryl means a group such as phenyl and naphtyl.
The process of the present invention is described in detail below. ##STR5## In the formulae, X represents halogen, and R.sup.1, R.sup.2, R.sup.3, and R.sup.4 have the same meanings as defined above.
The halogen means chlorine, bromine, or iodine.
The starting Compound (I) can be obtained according to the method described in Japanese Published Unexamined Patent Application No. 41489/85.
Compound (V) can be obtained by reacting Compound (I) with 1 to 20 equivalents of tri-substituted silyl chloride in the presence of 1 to 20 equivalents of a base such as triethylamine, pyridine and imidazole, in a solvent at -30.degree. to 50.degree. C. for 0.5 to 24 hours. As a solvent, a halogenated hydrocarbon such as methylene chloride, chloroform, ethylene dichloride and carbon tetrachloride, an ester such as ethyl acetate, isopropyl acetate, tert-butyl acetate, isobutyl acetate and butyl acetate, and dimethylformamide are used singly or in combination in an amount of 1 to 50-fold (by weight) based on Compound (I).
Compound (VI) can be obtained by reacting Compound (V) with 1 to 20 equivalents of alkyl halide in the presence of 1 to 20 equivalents of a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide and sodium hydride, in a solvent at -30.degree. to 50.degree. C. for 0.5 to 24 hours. As a solvent, dimethylformamide and dimethylsulfoxide are used singly or in combination in an amount of 1 to 50-fold (by weight) based on Compound (V).
Compound (II) can be obtained by treating Compound (VI) with 1 to 100 equivalents of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid, methane sulfonic acid, or the like, in a solvent or without a solvent. As a solvent, an
REFERENCES:
patent: 5013854 (1991-05-01), Bunnell
patent: 5084568 (1992-01-01), Bunnell
patent: 5344926 (1994-09-01), Murakata et al.
Bioorganic & Medicinal Chem. Letters, vol. 4, No. 11 (Jun. 1994) 1333-38.
Kasai Masaji
Kinugawa Masahiko
Masuda Yoshiaki
Mimura Yukiteru
Murakata Chikara
Kyowa Hakko Kogyo Co. Ltd.
Shah Mukund J.
Sripada Pavanaram K.
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