Process for the preparation of 2,3-Dihydroindoles...

Details Process for the preparation of 2,3-Dihydroindoles... Process for the preparation of 2,3-Dihydroindoles...

1999-11-18

2001-10-02

Solola, T.A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S490000, C548S491000

Reexamination Certificate

active

06297270

ABSTRACT:

A large number of indole derivatives, in particular of indole alkaloids, are employed as medicaments in human and veterinary medicine (E. Breitmaier “Alkaloide: Betäubungsmittel, Halluzinogene und andere Wirkstoffe” [Alkaloids: Anesthetics, Hallucinogens and Other Active Compounds], Teubner Studienbücher Chemie, 1997). 2,3-Dihydroindole derivatives are likewise of great pharmocological interest as active compounds. Moreover, they serve as starting materials for corresponding indoles, since they can be very simply dehydrogenated (cf. B. Robinson, Chem. Rev. 1969, 69, 785; and also Y. Kikugawa, M. Kashimura, Synthesis 1982, 785).
In the university field, frequently used methods for the synthesis of indoles and 2,3-dihydroindoles are Fischer's indole synthesis (B. Robinson, Chem. Rev. 1969, 69, 227) and the Reissert reaction (G. Blasko, P. Kerekes, S. Makleit, Alkaloids (Academic Press) 1987, 31, 1-28; J. G. Cannon, B. J. Demopoulos, J. P. Long, J. R. Flynn, F. M. Sharabi, J. Med. Chem. 1981, 238-40).
The multistage reaction sequences can only be carried out with difficulty and are therefore industrially unimportant.
An alternative to this is the cyclization of halogen-substituted N-(2-arylethyl)amines via aryne intermediates (R. Huisgen, H. König, Chem. Ber. 1959, 92, 203; R. Huisgen, H. König, N. Bleeker, Chem. Ber, 1959, 92, 424; H. König, R. Huisgen, Chem. Ber. 1959, 92, 429; H. lida, S. Aoyagi, C. Kibayashi, J. Chem. Soc., Perkin I 1975, 2502). The base employed in these reports is the compound phenyllithium, which is extremely reactive and difficult to handle industrially. The cyclization takes place only in yields of below 50%. As the 2-halophenylethylamines used as starting materials can only be obtained by a complicated multistage synthesis (total yields 13% and 18% respectively), this method also does not find any wide application.
The object of the present invention is the provision of a new preparation process for 2,3-dihydroindole derivatives which does not have the disadvantages of the known processes and is moreover suitable for carrying out on an industrial scale. A further object of the present invention is the provision of novel 2,3-dihydroindoles, and their use.
This object is achieved by a process for the preparation of 2,3-dihydroindoles of the formula (I)
in which the radicals R1 to R7 independently of one another are selected from the group consisting of hydrogen, fluorine, chlorine, (C
1
-C
8
)-alkyl, O-alkyl-(C
1
-C
8
), OCO-alkyl-(C
1
-C
8
), OH, NO
2
, Si(alkyl)
3
-(C
1
-C
8
), CF
3
, CN, COOH, CHO, SO
3
H, NH
2
, NH-alkyl-(C
1
-C
8
), N-alkyl
2
-(C
1
-C
8
), NH—Ar, NAr
2
, P-alkyl
2
-(C
1
-C
8
), SO
2
-alkyl-(C
1
-C
6
), SO-alkyl-(C
1
-C
6
), NHCO-alkyl-(C
1
-C
4
), COO-alkyl-(C
1
-C
8
), CONH
2
, CONH-alkyl-(C
1
-C
8
), CO-alkyl-(C
1
-C
8
), NHCOH, NHCOO-alkyl-(C
1
-C
4
), CHCH—CO
2
-alkyl-(C
1
-C
8
), CHCHCO
2
H, P-alkyl
2
-(C
1
-C
8
), POalkyl
2
-(C
1
-C
4
), PO
3
H
2
, PO(O-alkyl-(C
1
-C
6
))
2
, SO
3
-alkyl-(C
1
-C
4
), SO
2
-alkyl-(C
1
-C
6
), SO-alkyl-(C
1
-C
6
), Si(alkyl)
3
-(C
1
-C
8
), Ar, O—Ar, CO—Ar, COO—Ar, PO—Ar
2
and PAr
2
;
where Ar is
an aromatic radical having up to 14 carbon atoms; or
a heteroaromatic, selected from the group consisting of the five-, six- or seven-membered rings having at least one nitrogen, oxygen and/or sulfur atom in the ring;
by reaction of halostyrenes of the formula (IIa) or (IIb)
with amines of the formula (IIl)
R
1
—NH
2
  (III)
where in the formulae (IIa), (IIb) and (III)
R
1
to R
7
have the same meaning as in formula (I);
X is selected from the group consisting of chlorine, bromine, iodine, OSO
2
CF
3
, OSO
2
aryl-(C
6
-C
10
), OSO
2
alkyl-(C
1
-C
8
) and N
2
+
Y
−
, where Y is a chlorine, bromine or iodine atom or a tetrafluoroborate or tetraphenylborate anion;
in at least one inert solvent or in water and in the presence of at least one base, selected from the group consisting of
primary, seconary and tertiary alkoxides;
primary and secondary amides of alkali metal and/or alkaline earth metal elements;
alkyl and aryl compounds of alkali metals and/or alkaline earth metals; and
carbonates, hydroxides, hydrogencarbonates of lithium, sodium, potassium, calcium, magnesium and cesium.
According to a preferred embodiment, the radical R
1
can be a (C
1
-C
8
)-alkyl, phenyl, naphthyl, anthryl, phenanthryl, biphenyl, pyridine, pyrimidine, oxazole, imidazole, pyrazine, quinoline, indole, furan, benzofuran or thiophene radical.
According to a particularly preferred embodiment of the invention, the radicals R
2
to R
7
can independently of one another be selected from the group consisting of hydrogen, (C
1
-C
8
)-alkyl, O-alkyl-(C
1
-C
8
), O—CO-alkyl-(C
1
-C
8
), N-alkyl
2
-(C
1
-C
8
), Ar, F, Cl, NO
2
, CN, COOH, CHO, SO
2
-alkyl-(C
1
-C
4
), NH-alkyl-(C
1
-C
8
), NH—Ar, NAr
2
, COO-alkyl-(C
1
-C
8
), CONH
2
, CONH-alkyl-(C
1
-C
8
), CO—(C
1
-C
8
)-alkyl, CO—Ar and/or PO—Ar
2
; where Ar has the same meaning as described beforehand and is in particular a phenyl radical.
The radicals mentioned beforehand can also be substituted. Particularly preferred cases are those in which
the aromatic radical Ar has up to 5 substitutents;
the heteroaromatic has up to 4 substituents; and/or
the radical R
1
has up to 5 substituents,
which independently of one another are selected from the group consisting of fluorine, chlorine, CF
3
, OH, NO
2
, CN, R
5
, O—R
5
, CHO, CO—R
5
, COOH, COO—R
5
, OCO—R
5
, SiR
5
3
, NH
2
, NH—R
5
, N—R
5
2
, SO—R
5
, SO
2
—R
5
, SO
3
H, SO
3
—R
5
, CONH
2
, NHCOH, NHCO—R
5
, NHCOO—R
5
, CHCH—CO
2
-alkyl-(C
1
-C
8
), PO—R
5
2
, P—R
5
2
, PO
3
H
2
, PO(O-alkyl-(C
1
-C
6
))
2
and CHCHCO
2
H; where R
5
is an alkyl radical having 1 to 8 carbon atoms or an aryl radical Ar; where Ar has the same meaning as in claim
1
and is in particular a phenyl radical.
The process according to the invention is particularly suitable for the preparation of dihydroindoles in which the radical R
1
is a 4-fluorophenyl or 2-methoxyphenyl radical.
If the radical Ar is a heteroaromatic, up to four further aromatic, heteroaromatic and/or aliphatic rings can be fused to this heteroaromatic ring.
The starting materials necessary for the process, such as amines and 2- or 3-halostyrenes, are commercially available. Specific substituted halostyrenes can be simply prepared by the palladium-catalyzed Heck reaction or Wittig reaction, so that a large number of substrates are available for the process according to the invention.
In view of the generally known fact according to which aryne cyclizations of 2-halophenylethylamines proceed in only moderate yield (R. Huisgen, H. König, Chem. Ber. 1959, 92, 203; R. Huisgen, H. König, N. Bleeker, Chem. Ber, 1959, 92, 424; H. König, R. Huisgen, Chem. Ber. 1959, 92, 429; H. lida, S. Aoyagi, C. Kibayashi, J. Chem. Soc., Perkin I 1975, 2502), it was surprising that according to the process according to the invention any desired substituted 2,3-dihydroindoles can be obtained in good yield in only one stage starting from halostyrene derivatives and primary amines.
The base in the process can be selected from the group consisting of potassium alkoxides, cesium alkoxides, alkali metal amides, organolithium compounds and organomagnesium compounds. Preferentially, the base is selected from the group consisting of potassium tert-butoxide, potassium isopropoxide, sodium methoxide, potassium methoxide, sodium ethoxide, magnesium methoxide, calcium ethoxide, lithium diisopropylamide, lithium diethylamide, sodium dimethylamide, cesium carbonate, butyllithium, phenyllithium, phenylmagnesium chloride and potassium hydroxide.
The inert solvent can be selected from the group consisting of aromatic or aliphatic hydrocarbons, esters, amines and amides. Preferentially, the solvent is selected from the group consisting of THF (tetrahydrofuran), dioxane, diethyl ether, diglyme, MTBE (methyl tert-butyl ether), DME (dimethyl ether), toluene, xylenes, anisole, ethyl acetate, ethylene carbonate and propylene carbonate.
In the process according to the invention, in general th

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