Process for preparing heterocyclic indene analogs

Details Process for preparing heterocyclic indene analogs Process for preparing heterocyclic indene analogs

2002-01-22

2004-08-17

Chang, Ceila (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S439000, C548S440000, C548S441000, C548S444000, C548S508000, C548S562000, C549S052000, C549S466000, C549S430000, C568S013000, C568S017000, C556S143000

Reexamination Certificate

active

06777559

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The present invention is concerned with a novel process for the preparation of heterocyclic indene analogs, especially with the preparation of 4-hydroxycarbazole or N-protected 4-hydroxycarbazole. These compounds may be used as a building block for pharmaceutically active compounds, e.g. 1-(9H-carbazol-4-yloxy)-3-[[2-(2methoxy-phenoxy)ethyl]amino]-2-propanol (carvedilol). This compound is known in the art and is described for example in EP 0 004920. It is especially useful for prophylaxis and treatment of heart- and circulatory diseases like, for example, hypertension, coronary heart failure, angina pectoris and the like.
2. Description
Processes for the catalytic cyclocarbonylation of pyrrole and indole derivatives have been described by Hiday et al., Advances in Metal-Organic Chemistry, Volume 4, 275-309. These processes are characterized by high temperatures, high catalyst loadings and modest selectivity. Moreover, the educts necessary for the reactions in these processes are expensive, since they have to be prepared by lengthy procedures, and are not available commercially.
Surprisingly, it has been found that using the process according to the present invention, heterocyclic indene analogs, e.g. indole or carbazole derivatives (such as 4-hydroxycarbazole and N-protected 4-hydroxycarbazole) can be prepared from commercial educts and without the aforementioned disadvantages.
SUMMARY OF THE INVENTION
The subject invention provides a process preparing a compound of the formula:
wherein
R
1
and R
2
are independently selected from the group consisting of hydrogen and lower-alkyl; or
R
1
and R
2
together with the ring carbon atoms to which they are attached form a monovalent carbocyclic or a monovalent carbocyclic aromatic ring or a monovalent carbocyclic or monovalent carbocyclic aromatic ring may substituted by halogen, lower-alkyl or lower-alkoxy;
X is O, S or N—Z;
Z is an amino protecting group selected from the group consisting of SO
2
R
a
, NMe
2
, CO
2
R
b
and CON(R
c
)
2
;
R
a
is lower-alkyl or aryl; and
R
b
and R
c
are lower-alkyl.
This process comprises:
cyclocarbonylating a compound of formula:
 wherein R
3
is lower-alkyl, aryl or aralkyl, and R
1
, R
2
and X are as defined above;
to form a compound of formula:
 wherein R
4
is lower-alkyl or aryl and R
1
, R
2
and X are as defined above; and
saponifying the compound of formula (III) to produce the compound of formula (I).
It is favored where X is N—Z or Z is SO
2
R
a
and R
a
is phenyl. It is also favored where R
1
and R
2
together with the ring carbon atoms to which they are attached form a phenyl ring. Another favored embodiment is where R
3
is methyl or phenyl.
Beneficially, the cyclocarbonylating is carried out in the presence of a base, an anhydride, and a catalyst comprising a transition metal compound and a ligand. Preferred transition metal compounds are palladium salts, such as Pd(OAc)
2
, Pd
2
dba
3
, PdCl
2
, Pd
2
Cl
2
(&pgr;-allyl)
2
, PdCl
2
(NCMe)
2
, [Pd(NCMe)
4
](BF
4
)
2
or Pd/C. Pd(OAc)
2
is favored.
The ligand can be P(R
5
)(R
6
)(R
7
) or (R
5
)(R
6
)P—(Y)—P(R
5
)(R
6
) wherein R
5
, R
6
and R
7
each independently are C
1-8
-alkyl, cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted by C
1-4
-alkyl, C
1-4
-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxy or phenyl and Y is binaphthyl, 6,6′-dimethyl- or 6,6′-dimethoxybiphenyl-2,2′-diyl, or one of the groups—(CH
2
)
n
—, —CH
2
CH
2
—P(C
6
H
5
)—CH
2
CH
2
—,
and n is a number of 1-8. A preferred ligand is selected from the group consisting of triphenylphosphine, and
More favored is triphenylphosphine,
The cyclocarbonylating can be carried out in the presence of a base selected from the group consisting of tri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines, sodium hydroxide, potassium hydroxide or salts of carbonic acids. Presently, triethylamine is favored.
Anhydrides such as (R
4
(C═O))
2
O, wherein R
4
is as defined above are preferred. Favored anhydrides include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride, and benzoic anhydride.
Saponifying is can be performed in a biphasic mixture of sodium hydroxide in toluene or in a homogeneous mixture of sodium methylate in methanol.
A more favored process is where the cyclocarbonylating is carried out in the presence of a base selected from the group consisting of tri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines, sodium hydroxide, potassium hydroxide and salts of carbonic acids. An anhydride of the formula (R
4
(C═O))
2
O, wherein R
4
is as defined as above is used. In addition, a catalyst comprising a transition metal compound and a ligand is provided. The transition metal compound is selected from the group consisting of Pd(OAc)
2
, Pd
2
dba
3
, PdCl
2
, Pd
2
Cl
2
(&pgr;-allyl)
2
, PdCl
2
(NCMe)
2
, [Pd(NCMe)
4
](BF
4
)
2
, and Pd/C. The ligand is selected from the group consisting of P(R
5
)(R
6
)(R
7
) and (R
5
)(R
6
)P—(Y)—P(R
5
)(R
6
) wherein R
5
, R
6
and R
7
each independently are C
1-8
-alkyl, cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted by C
1-4
-alkyl, C
1-4
-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxy or phenyl and Y is binaphthyl, 6,6′-dimethyl- or 6,6′-dimethoxybiphenyl-2,2′-diyl, or one of the groups —(CH
2
)
n
—, —CH
2
CH
2
—P(C
6
H
5
)—CH
2
CH
2
—,
and n is a number of 1-8.
All combinations of the above bases, anhydrides, and catalysts are envisioned, as are the choices of ligands, transition metal compounds and saponifying agents.
The subject invention also provides a compound of formula:
wherein R
8
is hydrogen, acetyl or benzoyl.


REFERENCES:
patent: 6291685 (2001-09-01), Junghans et al.
patent: 1 078 923 (2000-07-01), None
Hiday, et al., Advances in Metal-Organic Chemistry, vol. 4, pp. 275-309, 1995.
Masakazu Iwasaki et al., Journal of Organic Chemistry, vol. 56, 1991, pp. 1922-1927.

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