Method for producing 3-alkanoylindoles and 3-alkylindoles

Details Method for producing 3-alkanoylindoles and 3-alkylindoles Method for producing 3-alkanoylindoles and 3-alkylindoles

2001-06-11

2003-01-21

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06509475

ABSTRACT:

This application is a 371 of PCT/EP99/09334 filed Dec. 1, 1999.
The invention relates to a process for the preparation of compounds of the formula I.
in which
R is Hal or methyl,
R
1
, R
2
are in each case independently of one another H, A′, aryl, NH
2
, NHA″, N(A″)
2
, COOA′″, CN or Hal,
X is O or H,H,
A′, A″, A′″ are in each case independently of one another alkyl having 1-6 carbon atoms,
Hal is F, Cl, Br or I and
n is 1, 2, 3, 4, 5 or 6,
and their acid addition salts, characterized in that
a) if X is O and R, R
1
, R
2
and n are as defined above, a compound of the formula II
in which
R
1
, R
2
are in each case independently of one another H, A′, aryl, NH
2
, NHA″, N(A″)
2
, COOA′″, CN or Hal.,
A′, A″, A′″ are in each case independently of one another alkyl having 1-6 carbon atoms and
Hal is F, Cl, Br or I,
is reacted with a compound of the formula III
 R—(CH
2
)
n
—CO—L  III
in which
R is Hal or methyl,
L is Cl, Br, I, OH or a free OH group or an OH group which has been functionally modified to be reactive,
Hal is F, Cl, Br or I and
n is 1, 2, 3, 4, 5 or 6,
in a Friedel-Crafts acylation with catalysis of Lewis acid metal halides of the type R′—Al(Cl)
2
,
in which
R′ is A or aryl′,
A is alkyl having 1-6 carbon atoms,
aryl′ is unsubstituted phenyl or phenyl mono- or disubstituted by A′, OA′ or Hal,
Hal is F or Cl,
or
b) if X is H,H and R, R
1
, R
2
and n are as defined above,
a compound of the formula I in which X is O or R, R
1
, R
2
and n are as defined above,
is reduced using complex hydrides with activation by Lewis acid metal halides of the type R′—Al(Cl)
2
,
in which
R′ is A or aryl″,
A is alkyl having 1-6 carbon atoms,
aryl′ is unsubstituted phenyl or phenyl mono- or disubstituted by A′, OA′ or Hal,
Hal is F or Cl,
and/or in that a resulting base of the formula I is converted into one of its acid addition salts by treatment with an acid.
Processes for the preparation of acylated indoles are known, described, for example, by M. Tani et al., Chem. Pharm. Bull. 38 (12) 3261-3267 (1990), where the indole ring is substituted in the 2-position by ethoxycarbonyl.
A process for the preparation of methyl-3-(4-chloro-1-oxobutyl)-5-indolecarboxylate under AlCl
3
catalysis is described by Böttcher et al. in Liebigs Ann. Chem. 1988, 749-752.
In J. Med. Chem. 1980, 23, 1306-1310, an indole acylation via intermediate MgX salts of indole with R-CO-X is described by C. Gueremy.
In Tetrahedron Letters 28 (32), 3741-3744 (1987), an indole acylation via intermediate MgX salts is also described, by J. Bergmann et al.
Another acetylation 5-cyanoindole with acetyl chloride with catalysis of SnCl
4
is described by Agarwal et al. in Synthetic Communications 23 (8), 1101-1110 (1993).
The reduction of 4-indol-3-yl-4-oxobutyric acid using LiAlH
4
is described by J. S. L. Ibaceta-Lizana in J. Chem. Soc. Perkin Trans. II 1987, 1221-1226.
The reduction of a 3-alkanoylindole ester using NaBH
4
/BF
3
ether is described by Böttcher et al. in Liebigs Ann. Chem. 1988, 749-752.
Another reduction of a phthalimide derivative of 3-acetyl-5-cyanoindole using NaBH
4
under isopropanol catalysis is described by Agarwal et al. in Synthetic Communications 23 (8), 1101-1110 (1993).
Surprisingly, investigations for the purposes of the synthesis of medicaments, which are described, for example, in DE 43 33 254 (EP 0 648 767), have shown that the compounds of the formula I can be obtained in at least comparable or higher yield compared with the prior art, the decisive advantages in this connection being the simple reaction which is carried out in homogeneous phase, and simple product isolation which is possible as a result.
As a consequence, this also means a lower consumption of solvent and energy.
For example, for the preparation of compounds of the formula I in which X is O, in the acylation according to step a), the catalyst, for example liquid isobutylaluminium dichloride (i-Bu-AlCl
2
), can be introduced used and undiluted using a pump. The formation of virtually insoluble and nonstirrable solidS components, known from the prior art and often triggered under AlCl
3
catalysis, does not occur. Another advantage which can be mentioned is the appearance of fewer by-products since, for example, said i-Bu-AlCl
2
acts as a weaker Lewis acid than AlCl
3
, and activation of a chloroalkyl function in the side chain and a Friedel-Crafts alkylation derived there from, as secondary reaction, is heavily suppressed.
Also in the reduction according to the invention as in step b) of the compounds of the formula I in which X is O, to give the compounds of the formula I in which X is H,H, advantages which can be mentioned are yields which are comparable to or higher than the prior art, coupled with the fact that the reaction is easier to carry out and the product is easier to isolate. A further advantage which can also be mentioned here is -he appearance of fewer by-products, particularly when reduction-sensitive substituents such as CN or ester groups are in positions 4 and 7 of the indole.
According to the process of the invention, the compound 3-(4-chlorobutanoyl)indole-5-carbonitrile is, for example, prepared in particular, which is then converted to the compound 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine, disclosed in DE 43 33 254.
The invention therefore relates in particular to a process for the preparation of compounds of the formula I
in which
R is Hal,
R
1
is H,
R
2
is CN,
x is O or H,H,
Hal is F, Cl, Br or I and
n is 2, 3 or 4,
and their acid addition salts, characterized in that
a) if X is O and R, R
1
, R
2
and n are as defined above,
a compound of the formula II
in which
R
1
is H and
R
2
is CN,
is reacted with a compound of the formula III
R—(CH
2
)
n
—CO—L  III
in which
R is Hal,
L is Cl, Br, I, OH or a free OH group or an OH group which has been functionally modified to be reactive,
Hal is F, Cl, Br, I and
n is 2, 3 or 4,
in a Friedel-Crafts acylation with catalysis of Lewis acid metal halides of the type R′—Al(Cl)
2
,
in which
R′ is A,
A is alkyl having 1-6 carbon atoms,
or
b) if X is H,H and R, R
1
, R
2
and n are as defined above,
a compound of the formula I in which X is O and R, R
1
, R
2
and n are as defined above,
is reduced using complex hydrides with activation by Lewis acid metal halides of the type R′—Al(Cl)
2
,
in which
R′ is A,
A is alkyl having 1-6 carbon atoms,
and/or in that a resulting base of the formula I is converted into one of its acid addition salts by treatment with an acid.
The compounds of the formula I in which X is O and which are reduced in step b) can in principle also be obtained by customary processes by acylation under, for example, AlCl
3
catalysis. However, they are preferably prepared as in reaction step a) and then reduced as in step b).
The invention therefore preferably provides a process according to the two processes mentioned, for the preparation of compounds according to formula I in which X is H,H and R, R
1
, R
2
and n are as defined above, characterized in that the compounds of the formula I in which X is O and R, R
1
, R
2
and n are as defined above, are prepared as in step a) and then reduced as in step b)
A′, A′ and A′″ are alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, preference being given in particular to, for example, methyl or ethyl, but also propyl, isopropyl, and also butyl, isobutyl, sec-butyl or tert-butyl.
R in the compounds of the formulae I and III is preferably Cl or methyl.
In the compounds of the Lewis acid metal halides of the type R′—Al(Cl)
2
, R′ is preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, isopentyl, phenyl, o-, m- or p-tolyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorine, o-, m- or p-chlorophenyl. Very particularly preferably, R&prim

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