Substituted Amides of 9-Hydroxy- and 9-Bromofluorene-4-carboxylic Acids
Abstract Generated abstract
This paper reports the synthesis of substituted amides of 9-hydroxyfluorene-4-carboxylic acid and 9-bromofluorene-4-carboxylic acid as intermediates for potential adrenoblocking medicinal compounds. Motivated by efforts to obtain analogs related to dibenamine with reduced toxicity and retained physiological activity, the work introduces acylamide-containing fluorene derivatives that could be converted to quaternary ammonium compounds. The experimental procedures involve reduction of substituted 9-fluorenone-4-carboxamide derivatives with zinc in ammoniacal ethanol to give hydroxy compounds, followed by bromination with hydrobromic acid in acetic acid. Ten previously undescribed compounds are listed with yields, melting points, empirical formulas, and nitrogen analyses.
Full Text
Substituted Amides of 9-Hydroxy- and 9-Bromofluorene-4-carboxylic Acids
G. M. Stepnova, Z. D. Skakun
(Presented by the scientific seminar of the Faculty of Chemical Technology)
The most interesting representative of adrenergic-blocking agents is dibenamine [1].
In therapeutic doses it is a strong vasodilating agent,
\[ \left[ \begin{array}{c} \mathrm{C_6H_5{-}CH_2} \\ \quad \backslash \\ \mathrm{NH^{+}{-}CH_2CH_2Cl} \\ \quad / \\ \mathrm{C_6H_5{-}CH_2} \end{array} \right]\mathrm{Cl^{-}} \]
capable of relieving many symptoms of frostbite, thrombophlebitis, Raynaud’s syndrome, and other pathological conditions.
The drawback of dibenamine is its high toxicity. In an attempt to obtain more active and less toxic compounds, many variants of the dibenamine structure [2] were synthesized, among them ethyl-9-fluorenyl-β-chloroethylammonium chloride.
\[ \left[ \begin{array}{c} \mathrm{fluorenyl{-}NH^{+}{-}CH_2CH_2Cl} \\ \quad | \\ \mathrm{C_2H_5} \end{array} \right]\mathrm{Cl^{-}} \]
This compound is ten times more active than dibenamine and less toxic.
As is known, the presence of an acylamide grouping of atoms in the molecule of a medicinal preparation, in a number of cases, gives rise to high activity and low toxicity. It may be hoped that introduction of this group into the molecule of ethyl-9-fluorenyl-β-chloroethylammonium chloride will lead to a reduction in toxicity while retaining high physiological activity. Earlier, we synthesized substituted amides of 9-fluo-
Table 1
Properties of the synthesized compounds
| No. | Compound name | Yield, % | mp, °C | Empirical formula | Nitrogen, % found | Nitrogen, % calculated |
|---|---|---|---|---|---|---|
| 1 | Naphthylamide of 9-hydroxyfluorene-4-carboxylic acid | 48 | 215–216 | \( \mathrm{C_{24}H_{17}O_2N} \) | 3.75 | 3.98 |
| 2 | o-Toluidide of 9-hydroxyfluorene-4-carboxylic acid | 56 | 189–190 | \( \mathrm{C_{21}H_{17}O_2N} \) | 4.86 | 4.44 |
| 3 | m-Toluidide of 9-hydroxyfluorene-4-carboxylic acid | 55 | 200–201 | \( \mathrm{C_{21}H_{17}O_2N} \) | 4.33 | 4.44 |
| 4 | m-Nitroanilide of 9-hydroxyfluorene-4-carboxylic acid | 53 | 203–204 | \( \mathrm{C_{20}H_{14}ON_2} \) | 7.95 | 8.09 |
| 5 | p-Nitroanilide of 9-hydroxyfluorene-4-carboxylic acid | 52 | 215–216 | \( \mathrm{C_{20}H_{14}ON_2} \) | 7.84 | 8.09 |
| 6 | Naphthylamide of 9-bromofluorene-4-carboxylic acid | 48 | 215–216 | \( \mathrm{C_{24}H_{16}ONBr} \) | 3.20 | 3.39 |
| 7 | o-Toluidide of 9-bromofluorene-4-carboxylic acid | 55 | 189–190 | \( \mathrm{C_{21}H_{16}ONBr} \) | 3.62 | 3.74 |
| 8 | m-Toluidide of 9-bromofluorene-4-carboxylic acid | 55 | 200–201 | \( \mathrm{C_{21}H_{16}ONBr} \) | 3.50 | 3.74 |
| 9 | m-Nitroanilide of 9-bromofluorene-4-carboxylic acid | 50 | 203–204 | \( \mathrm{C_{20}H_{13}O_3N_2Br} \) | 7.1 | 6.80 |
| 10 | p-Nitroanilide of 9-bromofluorene-4-carboxylic acid | 50 | 215–216 | \( \mathrm{C_{20}H_{13}O_3N_2Br} \) | 6.95 | 6.80 |
renone-4-carboxylic acid [3]. From these compounds it is possible to proceed rather readily to quaternary ammonium compounds of the general formula with possible adrenolytic activity.
\[ \left[ \mathrm{Ar{-}NH{-}OC{-}} \begin{matrix} \text{fluorene nucleus} \end{matrix} \mathrm{{-}\overset{+}{N}H(Alk){-}CH_2CH_2Cl} \right]\mathrm{Cl}^{-} \]
The aim of the present work is the synthesis of intermediates for the above-mentioned compounds.
Experimental Part
Synthesis of substituted amides of 9-hydroxyfluorene-4-carboxylic acid
In a flask equipped with a reflux condenser and a stirrer, 0.1 g-mol of the substituted amide of 9-fluorenone-4-carboxylic acid and 0.3 g-mol of zinc dust are heated for 30 min on a boiling water bath in a medium of 10% ammonia solution in the presence of ethyl alcohol. After cooling, the mixture is filtered; the precipitate is washed with ammonia solution and then with water, dried, and recrystallized from alcohol to a constant melting point.
Synthesis of substituted amides of 9-bromofluorene-4-carboxylic acid
0.1 g-mol of the substituted amide of 9-hydroxyfluorene-4-carboxylic acid is suspended in glacial acetic acid, an excess of hydrobromic acid is added, and the mixture is heated on a boiling water bath for 1–1.5 h. After cooling, the precipitate is filtered off and washed with water. The mother liquor is diluted with water, whereby an additional amount of product precipitates. The amide is recrystallized from alcohol or from xylene.
The properties of the compounds obtained are given in the table.
Conclusion
Substituted amides of 9-hydroxy- and 9-bromofluorenecarboxylic acids, not described in the literature, have been synthesized as intermediates for the synthesis of adrenoblocking medicinal preparations.
LITERATURE
- Nicherson, Goodman, J. Pharm. Exp. Therap., 89, 167, 1947.
- Loew, Aschenbach, Micetich, J. Pharm. Exp. Therap., 97, 441, 1949.
- L. P. Kulev, G. M. Stepnova, L. V. Kovalenok, P. F. Tabinskaya, Izv. SO AN SSSR, No. 12, 137, 1962.