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Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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Reexamination Certificate

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06573386

ABSTRACT:

This application is a 371 of PCT/HU00/00081, filed Jul. 13, 2000
Spiro[(4-cyclohexanone)-[3H]indol-2′[1′H]-one and dispiro[(1,3-dioxolan)-
2,-4
′-cyclohexane-3H]indol]-2″[1″H]-one derivatives are important intermediates to the vasopressine V
2
antagonistic compound, SR 121463. For example, as described in patent application WO 9715556 the dispiro[(1,3-dioxolan)-2,4′-cyclohexane-
1,-3
″-(5″-ethoxy)-[3H]indol]-2″[1″H]-one (compound of formula VII)
can be prepared by reacting 4-ethoxyphenylhydrazine with 4-(1, 3-dioxolan)cyclohexane-carboxylate sodium salt followed by cyclization of the resulting 1-(4′-ethoxyphenyl)-2-(4″-/1,3-dioxolan/-cyclohexane-carbonyl)-hydrazine.
According to another synthetic route (EP 636608) the compound of formula VII is obtained by oxidation of the spiro[(4-hydroxy-cyclohexane)-1,3′(5′-ethoxy)-[3H]indol-2′[1′H]-one to the appropriate cyclohexanone derivative, from which the ketal of the formula VII is prepared by reaction with ethylene glycol.
Disadvantages of both of the above syntheses are the toxic starting materials, many-step syntheses, low yields of some synthetic steps, expensive reagents and extreme reaction conditions in certain reactions.
To our surprise, we have found that in contrast to the analogous reaction described in the literature (Annalen 1941, 548, 117-146; J. Am. Chem. Soc. 1953, 75, 5301-5305; J. Chem. Soc. C, 1970, 796-800, J. Med. Chem. 1993, 36, 2459-2469) the addition of methyl or ethyl acrylate to 5-ethoxy-indolinone, followed by Dieckmann-condensation, hydrolysis and decarboxylation does not lead to a homogeneous product, that is why the procedures described in the literature above are not suitable for industrial synthesis. We have found that the hydrogen in position-1 of the 5-ethoxy-indolinone has to be substituted by an appropriate protective group, if we want the subsequent reactions to proceed in the desired direction.
In the case the substituent in position-1 is a phenyl group as described in U.S. Pat. No. 3,395,156 side reactions cannot be avoided. Before the Dieckmann-condensation the obtained 1-phenyloxindole-3,3-dipropionic acid ester has to be hydrolyzed and reesterified to get a pure starting material.
The subject of our invention is a process for the preparation of spiro [(4-cyclohexanone)-[3H]indol]-2′[1′H]-one derivatives of the general formula I
—wherein R
1
and R
2
independently stand for hydrogen, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
altkylthio, C
1-4
polyfluoroalky, C
1-4
polyfluorbalkoxy, C
3-7
cycloakyloxy, C
3-7
cycloalkylthio, phenoxy, benzyloxy or nitro group—,
characterized by reacting an indolin-2-one derivative of the general formula II
—wherein R
1
and R
2
are as defined above—with a compound capable for introducing a protective group, selected from 2-tetrahydropyranyl, 1-diethoxy-methylene or C
1-4
alkoxycarbonylethyl group, coupling the compound of general formula III,
thus obtained—wherein R
1
and R
2
are as defined above and A stands for a protective group, selected from 2-tetrahydropyranyl, 1-diethoxy-methylene or C
1-4
alkoxycarbonylethyl group—with an acrylic acid C
1-4
ester, cyclizing the resulting compound of the general formula IV
—wherein R
1
, R
2
and A are as defined above, R
3
stands for C
1-4
alkyl group—, eliminating the —COOR
3
group and the A protective group of the keto-ester of general formula V
—wherein R
1
, R
2
, R
3
and A are as defined above, optionally without isolation of the compounds of the general formulae IV
As for compounds capable to introduce the A protective group 2,3-dihydropyrane, triethyl orthoformate or an acrylic acid C
1-4
ester can be applied.
The reaction of the compound of general formula II
—wherein R
1
and R
2
are as defined above—with the compound capable to introduce the A protective group is preferably carried out in the presence of a catalyst, preferably in the presence of ptoluenestilfonic acid. As for solvent halogenated hydrocarbons, preferably dichioromethane can be used.
The reaction of the compounds of general formulae II
—wherein R
1
, R
2
and A are as defined above—with the acrylic acid C
1-4
ester is carried out in the presence of a catalyst, preferably in the presence of an alkali alcoholate, favorably sodium alcoholate.
Cyclization of the compounds of general formula IV
is carried out in the presence of an alkali alcoholate, preferably in the presence of sodium ethylate, potassium t-butylate.
Using acrylic acid C
1-4
ester for protective group, the process can advantageously performed as a “one pot” method, in a polar solvent, in the presence of a base.
Compounds of the general formulae III,
—wherein R
1
,R
2
,R
3
and A are as defined above—are new compounds, with the proviso, that in compound IV, if R
1
and R
2
stand for hydrogen, A is different from methoxycarbonyl-ethyl group.


REFERENCES:
patent: 3395156 (1968-07-01), Wolf et al.
patent: 5994350 (1999-11-01), Foulon et al.
patent: WO 97 15556 (1997-05-01), None
R.S. Johnson et al; “The Alkaloids of Gelsenium sempervirens. Part IV. Derivatives of pyridine, isoquinoline, and indol-2(3H)-one as possible initial materials for synthesis of Gelsemine”; Journal of the Chemical Society, Section C: Organic Chemistry; 1970, pp 796-800.
Andrew M. Thompson et al; “Tyrosine Kinase Inhibitors. 1. Structure-Activity Relationships for Inhibition of Epidermal Growth Factor Receptor Tyrosine Kinase Activity by 2,3-Dihydro-2-thioxo-1H-indole-3-alkanoic acids)”; Journal of Medicinal Chemistry, vol. 36, No. 17, 1993, pp 2459-2469.

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