Certain substituted cyclopentanone ethylene ketal compounds, and ketones and amides derived therefrom are useful synthetic intermediates for compounds of pharmaceutical interest. A synthetic process for using the intermediates is also described.

TECHNICAL FIELD 
This invention relates to substituted cyclopentane compounds and a 
synthetic process useful in the preparation of compounds of pharmaceutical 
interest. 
BACKGROUND OF THE INVENTION 
Esters of benzoic acid which are substituted on the aromatic ring by 
1,1-dihydroperfluoroalkoxy substituents and exhibit anesthetic activity 
are described in U.S. Pat. No. 3,655,728. Amides of benzoic acid which are 
substituted on the aromatic ring by 1,1-dihydroperfluoroalkoxy 
substituents and exhibit antiarrhythmic activity are described in U.S. 
Pat. No. 3,719,687. U.S. Pat. Nos. 3,900,481, 4,071,524 and 4,097,481 
describe antiarrhythmic agents including, inter alia, 
N-(piperidylmethyl)benzamides substituted by one or more 
1,1-dihydroperfluoroalkoxy groups. Above-mentiond U.S. Pat. No. 3,900,481 
discloses the compound 
2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide, a 
particularly useful antiarrhythmic agent also known as flecainide. An 
article appearing in the Journal of Medicinal Chemistry, Vol. 20, pg. 821 
(1977), discloses many of the compounds described in the latter patents, 
and also discloses various additional compounds such as 
2-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamides in which the 
aromatic ring is substituted in the 5-position by a non-functional group, 
i.e., methyl, chloro or fluoro. 
U.S. Pat. No. 4,339,587 discloses 
5-hydroxy-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide and 
synthetic intermediates useful in the synthesis thereof. The compound 
5-hydroxy-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is a 
metabolite of flecainide and is useful as an intermediate in the synthesis 
of flecainide and as an antiarrhythmic agent itself. 
DETAILED DESCRIPTION OF THE INVENTION 
In one aspect, the present invention relates to compounds of Formula I 
##STR1## 
wherein R is selected from the group consisting of 
##STR2## 
--CH.sub.2 NH.sub.2, 
##STR3## 
In another aspect, the present invention relates to compounds of Formula II 
##STR4## 
wherein A is selected from --CH.sub.2 CF.sub.3 and --CH.sub.2 .phi.; and Q 
is selected from 
##STR5## 
with the proviso that A is --CH.sub.2 CF.sub.3 when Q is 
##STR6## 
and A is --CH.sub.2 CF.sub.3 or --CH.sub.2 .phi. when Q is 
##STR7## 
The compounds of Formulas I and II are useful as synthetic intermediates in 
the preparation of 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
(a metabolite of flecainide) and 
2,5-bis(2,2,2-trifluoroethoxy)-N-(6-oxo-2-piperidylmethyl)benzamide. 
In still another aspect, the present invention relates to a process for 
preparing 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
and 2,5-bis(2,2,2-trifluoroethoxy)-N-(6-oxo-2-piperidylmethyl)benzamide 
using the above intermediates. 
Synthetic 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
is useful as a standard for monitoring the metabolism of flecainide in 
mammals. As for 
2,5-bis(2,2,2-trifluoroethoxy)-N-(6-oxo-2-piperidylmethyl)benzamide, it is 
believed that this compound could be reduced to provide flecainide and 
that it therefore is a useful synthetic intermediate. 
The following reaction scheme, wherein B is benzyl or --CH.sub.2 CF.sub.3, 
and B' is hydrogen (if B is benzyl) or --CH.sub.2 CF.sub.3 (if B is 
--CH.sub.2 CF.sub.3), illustrates a synthetic route by which the compounds 
of Formulas I and II may be obtained and the manner in which they may be 
used: 
##STR8## 
In step (1), known 2-oxocyclopentanecarboxylic acid ethylene ketal (Formula 
III) is converted to 2-oxocyclopentanecarboxamide ethylene ketal (Formula 
IV) under anhydrous conditions using a conventional mixed anhydride 
method. More particularly, the reactant is dissolved in a suitable inert 
solvent such as chloroform in the presence of an organic acid acceptor 
such as an organic amin (e.g., triethylamine) or an inorganic acid 
acceptor such as sodium carbonate or sodium bicarbonate. Ethyl 
chloroformate or an equivalent reactive blocking agent is added to the 
mixture, followed by addition of anhydrous ammonia to provide the amide of 
Formula IV. 
Alternatively, a simple lower alkyl ester of the compound of Formula III 
may be reacted with alcoholic ammonia by heating in a bomb to provide the 
amide of Formula IV. 
The amide of Formula IV is readily reduced in step (2) using a metal 
hydride reducing agent such as lithium aluminum hydride to provide 
(2-oxocyclopentane)methylamine ethylene ketal (Formula V) which may be 
readily converted to the amine salt by conventional methods. 
In step (3) the amine of Formula V is reacted with a known compound of 
Formula VI by heating in an inert solvent in the presence of an organic or 
inorganic acid acceptor such as those described above in connection with 
step (1). The product of step (3) is a compound of Formula VII. 
In step (4) the compound of Formula VII is converted by hydrolysis to the 
corresponding ketone of Formula VIII by heating in an aqueous alcohol such 
as aqueous ethanol in the presence of dilute strong acid such as 
hydrochloric acid. 
In step (5) the compound of Formula VIII is reacted in a conventional 
Schmidt-type reaction by reacting with hydrazoic acid in the presence of 
sulfuric acid in an inert solvent or solvent blend such as a chloroform 
and benzene mixture. Under these reaction conditions, if B of the compound 
of Formula VIII is benzyl, B' is hydrogen in the product of Formula IX. If 
B of the compound of Formula VIII is 2,2,2-trifluoroethyl, B' remains 
trifluoroethyl.

The following examples illustrate the preparation of the compounds of the 
invention. All temperatures in the examples are given in degrees 
Centigrade. 
EXAMPLE 1 
Preparation of the Compound of Formula IV 
To a solution of about 65 g of ammonia in 200 ml of methanol was added 20 g 
(0.10 mole) of ethyl 2-oxocyclopentanecarboxylate ethylene ketal. The 
mixture was heated at 130.degree. C. while shaking in a bomb for about 16 
hours. The mixture was then filtered and the solid residue discarded. The 
filtrate was evaporated, the resulting residue triturated with hexane, and 
the solid separated by filtration. The solid was dissolved in chloroform 
and passed through a chromatography column of florisil to provide 3.5 g of 
white solid after removal of solvent. This solid was recrystallized from 
toluene to provide fine white needles of 2-oxocyclopentanecarboxamide 
ethylene ketal, m.p. 134.degree.-136.degree. C. Analysis: Calculated for 
C.sub.8 H.sub.13 NO.sub.3 : %C, 56.1; %H, 7.65; %N, 8.2; Found: %C, 56.2; 
%H, 7.6; %N, 8.2. 
EXAMPLE 2 
Alternative Preparation of the Compound of Formula IV 
To a stirred, cold (0.degree. C.) solution of 1.72 g (0.01 mole) of 
2-oxocyclopentanecarboxylic acid ethylene ketal in 35 ml of chloroform was 
added first 1.11 g (0.011 mole) of triethylamine and then 1.085 g (0.01 
mole) of ethyl chloroformate, the latter being added in dropwise fashion. 
After stirring for 30 minutes, dry ammonia gas was bubbled in over about 5 
minutes. A white solid separated while the mixture was stirred at about 
0.degree. C. for 30 minutes. The solid was separated by filtration and 
washed with chloroform, and the combined washings and filtrate were 
evaporated to provide a white solid residue of 
2-oxocyclopentanecarboxamide ethylene ketal. Infrared spectral analysis 
showed the product to be identical to that obtained in Example 1. 
EXAMPLE 3 
Preparation of the Compound of Formula V 
To a stirred suspension of 8.11 g (0.218 mole) of lithium aluminum hydride 
in 50 ml of diethyl ether under nitrogen was added, in small portions, 
24.3 g (0.142 mole) of 2-oxocyclopentanecarboxamide ethylene ketal. The 
stirred mixture was heated at reflux for about one day, and the excess 
lithium aluminum hydride was then decomposed by adding sequentially and 
dropwise 8 ml of water, 12 ml of 10 percent aqueous sodium hydroxide 
solution, and an additional 20 ml of water. Filtration of the mixture 
followed by evaporation of the filtrate provided an oil. The oil was 
distilled to provide a clear, colorless liquid, b.p. 62.degree.-65.degree. 
C./0.4 mm of Hg, this being (2-oxocyclopentane)methylamine ethylene ketal. 
To a solution of 0.5 g of the ketal in 50 ml of diethyl ether was added 
diethyl ether which had previously been saturated with hydrogen chloride 
until the mixture was acid to litmus paper. The solid was separated by 
filtration, washed with ether and recrystallized from acetonitrile to 
provide white solid (2-oxocyclopentane)methylamine ethylene ketal 
hydrochloride, m.p. 144.degree.-146.degree.C. Analysis: Calculated for 
C.sub.8 H.sub.15 NO.sub.2.HCl: %C, 49.6; %H, 8.3; %N, 7.2; Found: %C, 
49.4; %H, 8.4; %N, 7.1. 
EXAMPLE 4 
Preparation of the Compound of Formula VII 
To a stirred suspension of 8.7 g (0.055 mole) of 
(2-oxocyclopentane)methylamine ethylene ketal, 17.6 g (0.166 mole) of 
sodium carbonate and 200 ml of benzene was added dropwise a solution of 
19.1 g (0.0553 mole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl 
chloride in 100 ml of benzene. The mixture was then heated to reflux and 
maintained at reflux for one hour. The mixture was evaporated, and water 
and diethyl ether were added to the residue. The layers were separated, 
and the organic layer was washed with saturated sodium chloride solution 
and dried over magnesium sulfate. The organic layer was evaporated to 
provide an off-white residue. Recrystallization of a sample of the solid 
residue from 2:1 heptane:benzene with treatment with decolorizing charcoal 
provided 5-benzyloxy-N-[(2-oxocyclopentane)methyl ethylene 
ketal]-2-(2,2,2-trifluoroethoxy)benzamide, m.p. 81.5.degree.-82.5.degree. 
C. Analysis: Calculated for C.sub.24 H.sub.36 F.sub.3 NO.sub.5 : %C, 61.9; 
%H, 5.6; %N, 3.0; Found: %C, 61.9; %H, 5.6; %N, 2.8. 
EXAMPLE 5 
Preparation of the Compound of Formula VIII 
To a solution of 24.3 g (0.0522 mole) of 
5-benzyloxy-N-[(2-oxocyclopentane)methyl ethylene 
ketal]-2-(2,2,2-trifluoroethoxy)benzamide in 300 ml of ethanol was added 4 
ml of 3N hydrochloric acid and 300 ml of water. The mixture was gradually 
heated to its reflux temperature and maintained at reflux for one hour. 
This mixture was cooled, 100 ml of water was added thereto, and the 
mixture was cooled with an ice bath. The white solid was separated by 
filtration and washed with cold water. A sample was recrystallized from 
1:1 heptane-toluene to provide 
5-benzyloxy-N-(2-oxocyclopentane)methyl-2-(2,2,2-trifluoroethoxy)benzamide 
, m.p. 105.degree.-107.degree. C. Analysis: Calculated for C.sub.22 
H.sub.22 F.sub.3 NO.sub.4 : %C, 62.7; %H, 5.3; %N, 3.3; Found: %C, 62.7; 
%H, 5.3; %N, 3.1. 
EXAMPLE 6 
Preparation of the Compound of Formula IX 
To a stirred, chilled (0.degree. C.) solution of 10 ml of concentrated 
sulfuric acid in 120 ml of chloroform was added dropwise a solution of 
15.5 g (0.0368 mole) of 
5-benzyloxy-N-(2-oxocyclopentane)methyl-2-(2,2,2-trifluoroethoxy)benzamide 
in 40 ml of chloroform and 28 ml of a 4 molar stock solution of hydrazoic 
acid in toluene. Stirring was continued for 1.5 hours at 0.degree. C. 
after the completion of the addition. Water (100 ml) was added to the 
solution, and the organic layer was separated and dried over magnesium 
sulfate, and then evaporated. The residue was triturated with hot toluene, 
and cooled. The solid was separated by filtration, recrystallized from 
ethyl acetate with treatment with decolorizing charcoal and cooled to 
provide 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide, 
m.p. 156.degree.-158.degree. C. Analysis: Calculated for C.sub.15 H.sub.17 
F.sub.3 N.sub.2 O.sub.4 : %C, 52.0; %H, 4.95; %N, 8.1; Found: %C, 51.5; 
%H, 5.1; %N, 7.7. The structural assignment was confirmed by comparison of 
infrared and nuclear magnetic resonance spectra to those of the same 
compound prepared by an alternative synthetic procedure which is described 
in copending application U.S. Ser. No. 551,967, filed of even date and 
commonly assigned.