Oxidative process and products thereof

Details Oxidative process and products thereof Oxidative process and products thereof

1999-09-23

2001-08-07

Kifle, Bruck (Department: 1611)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S576000

Reexamination Certificate

active

06271371

ABSTRACT:

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.
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
1
and X
2
are independently selected from H or a protecting group for the phenolic function, eg. acyl or trialkylsilyl; groups A
1
, A
2
, B
1
, B
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
1-20
alkyl, C
3-20
aryl or C
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.
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
1
and X
2
=H, R=Me, Z=Br and Y=COCF
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
1
, A
2
, B
1
, B
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
1
=A
2
=B
1
=B
2
=H and Y=COR, where R is H, C
1-20
alkyl, C
3-20
aryl, C
4-20
arylalkyl, C
1-20
alkyloxy; A
1
=A
2
=O, B
1
=B
2
=Y=H; B
1
=B
2
=O; A
1
=A
2
=Y=H, B
1
=B
2
=O; A
1
=A
2
=O, B
1
=B
2
=H and Y=Me; and A
1
=A
2
=H, B
1
=B
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
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
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° C.). Examples of suitable solvents include toluene, benzene, anisole, dibutyl ether, carbon tetrachloride, cyclohexane and pentane. Solvents that are particularly useful are aromatic hydrocarbons, and toluene is particularly preferred. Preferably, the reaction mixture is vigorously stirred, to ensure good mixing of components.
The process of the present invention is now illustrated by the following Examples.


REFERENCES:
patent: 4239605 (1980-12-01), Vlahov et al.
patent: 4290862 (1981-09-01), Vlahov et al.
patent: 6018043 (2000-01-01), Dyer et al.
patent: 6084094 (2000-07-01), Henshilwood et al.
patent: 401058 (1996-06-01), None
patent: 8808708 (1988-11-01), None
Kametani et al. (J. Chem. Soc. C (1971), 6, 1043-7).*
Szewczyk, J. et al. (1988) “An improved synthesis of galanthamine” J. Heterocyclic Chem. 25(6):1809-1811.
Kametani, T. et al. (1969) “Studies on the Syntheses of Heterocyclic Compounds. Part CCCXV. Modified Total Syntheses of (±)-Galanthamine through Phenol Oxidation” J. Chem. Soc., p. 2602-2605.
Vlahov, R. et al. (1989) “Synthesis of Galanthamine and Related Alkaloids—New Approaches. I.” Tetrahedron 45(11): 3329-3345.
Szewczyk, J. et al. (1995) “Facile synthesis of (+−), (+), and (−)-galanthamine” J. Heterocyclic Chem. 32(1):195-199.

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