Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1997-07-16
2000-07-04
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540576, C07D49106, C07C21758
Patent
active
060840943
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates a process for obtaining narwedine and derivatives thereof in improved yield
BACKGROUND
The phenolic oxidation of tyramine derivatives (1) to narwedine derivatives (2) is known with reagents such as potassium ferricyanide in a two phase system of chloroform and aqueous sodium hydrogen carbonate. The reaction typically gives a low yield and chromatographic purification is necessary; see for instance Szewczyk J., et al, J. Heterocyclic Chem. (1988) 25:1809, Kametani T., et al, J. Chem. Soc (C) (1969) 2602, and Vlahov R., et al, Tetrahedron No.11 (1989) 45:3329. ##STR1##
SUMMARY OF THE INVENTION
According to a first aspect of the present invention, a process for the preparation of a compound of formula (2) comprises phenolic oxidation of a compound of formula (1), both formulae being shown above, wherein X.sup.1 and X.sup.2 are independently selected from H or a protecting group for the phenolic function, eg. acyl or trialkylsilyl; groups A.sup.1, A.sup.2, B.sup.1, B.sup.2 and Y are selected so as to render the nitrogen atom non-basic; Z is a blocking group eg. Br or t-butyl; and R is H, C.sub.1-20 alkyl, C.sub.3-20 aryl or C.sub.4-20 arylalkyl, and wherein the process is carried out in a two phase liquid system comprising an aqueous base and an organic solvent having a dielectric constant below 4.8, as measured at 20.degree. C.
The process of the present invention is capable of producing the target compounds (2) in higher yields than achieved by prior art processes. In addition, the products are obtained in sufficient purity in the organic phase to be recoverable by evaporation, thereby avoiding chromatographic purification and significantly improving the economics of the process.
According to a second aspect of the present invention, novel compounds having the formula (2) above are provided, wherein X.sup.1 and X.sup.2 =H, R=Me, Z=Br and Y=COCF.sub.3 or CO-t-butyl. Such compounds are readily convertible to their corresponding galanthamine structures.
DESCRIPTION OF THE INVENTION
Broadly, the phenolic oxidation reaction which embodies the present invention is represented in Scheme 1 above. The substituents A.sup.1, A.sup.2, B.sup.1, B.sup.2 and Y in the starting material (1) are selected so as to render the nitrogen atom non-basic, thereby dictating that the requisite reaction take place. By non-basic typically we mean that the starting material includes a protecting group for the N-atom, eg. a carbonyl group, optionally as part of the basic skeleton linking the two aromatic rings. Suitable examples of these substituents include A.sup.1 =A.sup.2 =B.sup.1 =B.sup.2 =H and Y=COR, where R is H, C.sub.1-20 alkyl, C.sub.3-20 aryl, C.sub.4-20 arylalkyl, C.sub.1-20 alkyloxy; A.sup.1 =A.sup.2 =O, B.sup.1 =B.sup.2 =Y=H; B.sup.1 =B.sup.2 =O; A.sup.1 =A.sup.2 =Y=H, B.sup.1 =B.sup.2 =O; A.sup.1 =A.sup.2 =O, B.sup.1 =B.sup.2 =H and Y=Me; and A.sup.1 =A.sup.2 =H, B.sup.1 =B.sup.2 =O and Y=Me.
Z is a group that assists the formation of the target narwedine derivatives by blocking coupling at its position on the aromatic ring. Examples of Z include Br and .sup.t Bu, but Z can be any other blocking group desired in the narwedine derivative. R is typically a methyl group so as to provide narwedine itself, but it can be other alkyl, aryl, arylalkyl, etc., for instance of upto 20 carbon atoms, or R can be H. Further substitution may also be present where a more substituted narwedine derivative is required. For instance, either or both of the aromatic rings can include further substituents, such as further halogen atoms, typically in the ring including substituent X.sup.1.
The process of the invention is carried out in a two-phase liquid system comprising an aqueous base and an organic solvent having a dielectric constant less than that of chloroform, ie. less than 4.8 (as measured at 20.degree. C.). Examples of suitable solvents include toluene, benzene, anisole, dibutyl ether, carbon tetrachloride, cyclohexane and pentane. Solvents that are particularly useful are aromatic h
REFERENCES:
Szewcyk et al., J. Hetorocyclic Chem., 1988, 25, p. 1809, 1988.
Kametani et al., J. Chom. Soc., p. 2602, 1989.
Vlahov et al., Tetrahedron, No. 11, 45, p. 3329, 1989.
Henshilwood James
Johnson Nicholas Bernard
Janssen Pharmaceutica N.V.
Kifle Bruck
Shah Mukund J.
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