Note: Descriptions are shown in the official language in which they were submitted.
~Z~Q~
X-6172 -1-
IMPROVED SYNTHESIS OF 9-CARBAMOYL
9-(3-AMINOPROPYL~FLUORENES
A group of 9-aminoalkylfluorenes recently has
been disclosed as having valuable antiarrhythmic
activity; see U.S. Patent Nos. 4,197,313 and 4,277,495.
The 9-carbamoyl-9-aminoalkylfluorenes are among the most
interesting compounds, and one compound within this
group, namely 9-carbamoyl-9-(3-isopropylaminopropyl)-
fluorene, is now known generically as indecainide.
U.S. Patent No. 4,282,170 discloses a processfor preparing 9-carbamoyl-9-(3-aminopropyl)fluorene, an
intermediate in a synthesis of indecainide, which
process comprises hydrogenation of 9-carbamoyl-9-(2-
cyanoethyl)fluorene. The hydrogenation reaction is said
to be best carried out in an acidic medium, most
preferably in glacial acetic acid, although organic
solvents such as ethanol can be employed if desired.
We have now discovered that the hydrogenation
process described in U.S. Patent No. 4,282,170 leads to
formation of observable quantities of fluorene dimer and
trimer by-products, compounds of the formulas
(~ \CONH2 Cl~ \CONH2
~12 C~12
3 \CH2~NH \CH2,~N
.~",
....
~ Q~
X-6172 -2-
Removal of these by-products has proved extremely dif-
ficult, and in general they are carried through sub-
sequent reactions and can be found in the final product.
An object of this invention is to provide an
improvement in the process for hydrogenating 9-carbamoyl-
9-(2-cyanoethyl)fluorene. The improvement provided by
this invention results in reduced amounts of the afore-
mentioned fluorene dimer and trimer by-products being
produced, and thereby permits formation of a purer
pharmaceutical agent.
This invention concerns an improvement in a
process for converting a cyanoethylfluorene to an amino-
propylfluorene. The invention more particularly pro-
vides, in the process for preparing a compound of the
lS formula
R~ \7~
cll~ CONR R ( I )
(~H2
~Hz~H2
wherein R and Rl independently are hydrogen, Cl-C4
alkyl, fluoro or chloro; and R2 and R3 independently are
hydrogen or Cl-C6 alkyl, involving catalytically hydro-
genating a compound of the formula
~2~1018
X-6172 -3-
R ~
\CONR R
~H2
-N
wherein R and Rl are as previously defined, and
R4 and R5 independently are hydrogen or Cl-C6 alkyl,
the improvement comprising conducting the reaction in
the presence of an acid medium stronger than glacial
acetic acid.
In a preferred embodiment of this invention
the hydrogenation is carried out in the presence of
trifluoroacetic acid. In another preferred embodiment
the hydrogenation is carried out in the presence of a
mineral acid such as hydrochloric acid.
The process provided by this invention is
carried out by catalytically hydrogenating a 9-carbamoyl-
9-(2-cyanoethyl)fluorene in an acid medium stronger than
glacial acetic acid. As pointed out in U.S. Patent No.
4,282,170, the hydrogenation of the cyano group of a
cyanoethylfluorene can be accomplished employing any of
the common hydrogenation catalysts, including platinum,
palladium, nickel, rhodium and ruthenium. The process
generally will be carried out under a hydrogen pressure
of about 1 to about 4 atmospheres, and typically at a
temperature of about 20 to about 70C.
~2~
X-6172 _4_
The hydrogenation process of this invention
can be carried out in essentially any organic solventi
all that is required is that about one molar equivalent
or more of an acid stronger than glacial acetic acid be
present in the reaction mixture. Organic solvents that
can be employed include alcohols, ethers, aromatics,
amides, as well as organic or inorganic acids and
mixtures of acids. For example, the process is con-
veniently carried out in an alcohol such as methanol
or ethanol together with at least about one molar
quantity, relative to the cyanoethylfluorene to be
reduced, of a strong acid such as 12N hydrochloric acid
or the like.
Any acid that is stronger than acetic acid can
be employed in the process of this invention. Such
acids include those having a PKa less than about 4.75,
the PKa of glacial acetic acid at 25C. Preferred acids
have a pKa less than 2.0, most preferably less than 1.0
Exemplary of the strong acids that can be employed in
the present process include benzosulfonic acid, any of
the aminobenzosulfonic acids, ortho or meta-bromobenzoic
acid, trichloroacetic acid, the chlorobenzoic acids,
2-chlorophenoxyacetic acid, 3-chlorophenoxyacetic acid,
dimethylmalonic acid, dinicotinic acid, diphenylacetic
acid, fluorobenzoic acid, formic acid, fluoroacetic
acid, glycolic acid, hippuric acid, 2-hydroxybenzoic
acid, 2-iodobenzoic acid, itacomic acid, lutidinic acid,
maleic acid, malonic acid, mesaconic acid, methylmalonic
acid, naphthalenesulfonic acid, a-naphthoic acid, oxalic
acid, o-phthalic acid, quinolinic acid, sulfanilic acid,
~-tartaric acid, trichloroacetic acid, trifluoroacetic
~2~ 8
X-6172 -5-
acid, 2,4,6-trihydroxybenzoic acid, and similar strong
organic acid. Inorganic acids can also be employed and
exemplary of such acids are arsenic acid, chromic acid,
hydrofluoric acid, hydrochloric acid, iodic acid,
nitrous acid, periodic acid, phosphoric acid, pyrophos-
phoric acid, selenic acid, sulfuric acid, and related
strong inorganic acids.
While the mechanism of the present process is
not completely understood, it is believed that the
strong acid re~uired to be employed according to the
invention reacts with the primary amino group of the
9-(3-aminopropyl)fluorene as it is formed to produce an
acid addition salt. Once the primary amino group is
protonated ~s an acid addition salt, it is unavailable
for reaction with other reaction intermediates to
produce the dimer and trimer by-products.
The hydrogenation process of this invention
generally is substantially complete within about two to
about twenty-four hours when carried out at about
ambient temperature and under a hydrogen pressure of
about 1 to about 4 atmospheres. The 9-carbamoyl-9-
(3-aminopropyl)fluorene that is produced by the process
is readily isolated by established procedures if desired.
For example, the reaction mixture can be filtered to
remove the hydrogenation catalyst, and the reaction
solvent can be removed from the filtrate, for instance
by evaporation under reduced pressure. The aminopropyl-
fluorene product can be isolated and crystallized as an
acid addition salt, or if desired the salt can be
neutralized by reaction with a base such as sodium
hydroxide or ammonium hydroxide to provide the desired
~2~
X-6172 -6-
primary amine. That amine, or the acid-addition salt,
can be alkylated by conventional procedures, such as
those described in U.S. Patents Nos. 4,197,313 and
4,282,170.
Alternatively, in a preferred embodiment of
the invention the 9-carbamoyl-9-(3-aminopropyl)fluorene
is not isolated, but rather is reacted further in situ
to produce an N-alkyl derivative such as 9-carbamoyl-9-
(3-isopropylaminopropyl)fluorene. Such alkylation is
best accomplished by first neutralizing any excess acid,
for instance by addition of a base such as sodium bicar-
bonate, and then simply adding an aldehyde or a ketone
to the hydrogenation reaction mixture and subjecting the
mixture to further hydrogenation. The aldehyde or
ketone reacts with the primary amino group of the
9-carbamoyl-9-~3-aminopropyl)fluorene to produce the
corresponding Schiff base, which upon further hydro-
genation is reduced to the desired N-alkyl derivative.
For example, 9-carbamoyl-9-(2-cyanoethyl)fluorene can be
hydrogenated according to this invention by reaction
with hydrogen gas in the presence of a catalyst such as
platinum oxide and a strong acid such as trichloroacetic
acid to produce, substantially free of dimer or trimer
by-products, 9-carbamoyl-9-(3-aminopropyl)fluorene. The
reaction mixture is neutralized by addition of a base,
for example about one molar quantity or an excess of
sodium hydroxide or the like. A ketone such as acetone
can be added to the neutralized reaction mixture and the
mixture can be further hydrogenated to provide 9-
carbamoyl-9-(3-isopropylaminopropyl)fluorene. The
product thus produced is substantially free of undesired
by-products and can be isolated and purified by routine
procedures.
12~
X-6172 -7-
The process improvement provided by this
invention is further illustrated by the following
detailed examples. The examples are not intended to
limit the invention in any respect and should not be so
construed.
Example 1
A mixture of 100 g of 9-carbamoyl-9-(2-cyano-
ethyl)fluorene and 20 g of 5% palladium on charcoal in560 ml of tetrahydrofuran and 50 ml of water was stirred
at 100C for twenty-four hours under 1000 psi of hydro-
gen. The reaction mixture was filtered and the filtrate
was concentrated to dryness to provide 93.5 g of a white
lS solid identified as primarily dimer and trimer product.
The solid was suspended in 500 ml of acetone and the
mixture was stirred at 25C for one hour and then
filtered to give 34 g of a white solid. The filtrate
was concentrated to give 50 g of a white solid. The
white solids were combined and triturated in 675 ml
of hot tetrahydrofuran. The mixture was filtered and
the solvent was removed from the filtrate to give 69.9 g
of a white solid melting at 162.5-165C. The solid was
chromatographed twice over silica gel, eluting with
tetrahydrofuran, to give a substantially pure sample of
~24101~3
X-617Z' -8-
I~,i~,~, ~!
,C~ CONH2
¢H2
~H2
~H
~H2
~H2
~ ~ ~ CONH2
1S
Analysis calculated for C34H33N3O2
Theory: C, 79.19; H, 6.45; N, 8.15
20Found: C, 77.17; H, 6.33; N, 7.39.
Eight grams of the above dimer were added to
200 ml of ethyl acetate and 150 ml of methanol con-
taining 1.8 g of maleic acid. The reaction mixture was
heated at 100C for one hour and then cooled. The
crystalline precipitate was filtered and air dried to
give 9.8 g of 9,9'-(iminodi-3,1-propanediyl)bis[9H-
fluorene-9-carboxamidel(Z)-2-butene-dioate (1:1) having
the formula
12~
X-6172 -9-
f~
S (~ \CONH2
H2
H HO~I~CHI~H
H2
H2
(~ /CONHz
f~
M,P. 185-187C.
.nalysis calculated for C38H37N306
Theory: C, 72.25; H, 5.90; N, 6.65
Found: C, 71.97; H, 6.00; N, 6.40.
Example 2
A mixture of 15.02 g (57.2 mM) of 9-carbamoyl-
9-(2-cyanoethyl)fluorene and 4.0 g platinum oxide in
25 200 ml of glacial acetic acid was shaken at 25C under a
hydrogen atmosphere (4 atm) for three hours. The
reaction mixture was diluted by addition of 5.0 g
(86 mM) of acetone, and hydrogenation was continued for
an additional seventeen hours. The reaction mixture was
filtered and the filtrate was concentrated to dryness by
evaporation of the solvents under reduced pressure to
, . .
0~8
X-6172 -10-
give 32.0 g of a brown viscous oil. The oil was added
to 200 ml of ethyl acetate and 200 ml of ice water, and
this mixture was diluted by addition of 400 ml of 6N
hydrochloric acid. The aqueous acid layer was sep-
arated, made alkaline by addition of 110 ml of 50%
aqueous sodium hydroxide. The aqueous alkaline solution
was extracted several times with diethyl ether, and the
ethereal extracts were combined, washed with water,
dried and the solvent was removed by evaporation to give
13.4 g (76.1% yield) of product. The product was shown
by high performance liquid chromatography to be com-
prised of 83.4% 9-carbamoyl-9-(3-isopropylaminopropyl)-
fluorene and 8.2% of dimer, N,N-bis-[3-(9-carbamoyl-
fluoren-9-yl)propyl]amine, identical to that prepared
and characterized in Example 1.
Example 3
A solution of 10.1 g (38 mM) of 9-carbamoyl-
9-(2-cyanoethyl)fluorene in 190 ml of glacial acetic
acid and 3.3 ml of 12N hydrochloric acid containing
2.0 g of platinum oxide was shaken for six hours at 25C
in a Parr hydrogenator under 4 atm. of hydrogen. The
reaction mixture was neutralized by addition of 3.1 g
(38 mM) of sodium acetate,followed by addition of
8.34 ml of acetone. The reaction mixture was shaken for
an additional sixteen hours under 4 atm. of hydrogen.
An additional 2.75 ml of acetone were added to the
reaction mixture and it was shaken under hydrogen for
another two hours. The reaction mixture was filtered
~2~10~8
X-6172 -11-
and the filtrate was concentrated to 36.0 g of a viscous
liquid. The liguid was dissolved in 200 ml of water and
the aqueous solution was washed with diethyl ether and
then made alkaline by addition of 50% (w/v) aqueous
sodium hydroxide. The alkaline mixture was extracted
several times with diethyl ether and the ethereal
extracts were combined, washed with water and dried.
Removal of the solvent by evaporation under reduced
pressure afforded 9.6 g (82% yield) of a tan solid.
A solution of 9.4 g of the tan solid in 110 ml
of acetone was cooled to 0-5C and diluted bv addition
of 3 ml of 12N hydrochloric acid. The reaction mixture
was stirred at 0-5C for one hour, whereupon the white
precipitate that had formed was collected by filtration
and air dried to give 7.6 g of a product melting at
191-194C.
The product thus obtained was crystallized
from 90 ml of hot (80C) isopropanol to give 4.8 g of
9-carbamoyl-9-(3-isopropylaminopropyl)fluorene hydro-
chloride melting at 205-207C. High performance liquid
chromatography demonstrated the product to be at least
97.6% pure, with less than 1% of dimer being present.
Analysis calculated for C20H25ClN2O
Theory: C, 69.65; H, 7.31; N, 8.12
Found: C, 69.84; H, 7.47; N, 7.92.
NMR (DMSOd6): ~ 1.1 (d, 6H); 2.1-3.3 (m, 6H); 3.42
(s, lH); 6.3 ~s, lH); 7.0 (s, lH); 7.4-8.2 (m, 8H);
8.6-9.0 (broad s, 2H).
X-6172 -12-
ExamPle 4
A solution of 10.1 g of 9-carbamoyl-9-(2-
cyanoethyl)fluorene in 193 ml of glacial acetic acid and
8.66 g of trifluoroacetic acid containing 2.0 g of
platinum oxide was shaken for six hours under 4 atm. of
hydrogen in a Parr hydrogenation flask. The reaction
mixture was filtered and the filtrate was concentrated
to give 28.6 g of a viscous liguid. The liquid was
added to 200 ml of ice water and the aqueous mixture was
washed with dichloromethane. The aqueous layer was made
alkaline by addition of 50% (w/v) aqueous sodium hydroxide,
and the aqueous alkaline solution was extracted several
times with dichloromethane. The organic extracts were
combined, washed with water, dried, and the solvent was
removed by evaporation under reduced pressure to give
9.9 g (97% yield) of a tan solid identified by thin
layer chromatography as 9-carbamoyl-9-(3-aminopropyl)-
fluorene.
A solution of 9.1 g of the product from above
in 190 ml of ethanol and 8.34 ml (6.66 g, 114 mM) of
acetone containing 2.0 g of 5% palladium on charcoal was
shaken for twenty hours at 25C under 4 atm of hydrogen.
The reaction mixture was filtered and the filtrate was
concentrated to 13.1 g of a viscous liquid. The liguid
was added to 200 ml of water and 200 ml of diethyl
ether. The aqueous layer was separated, made alkaline
by addition of 50% sodium hydroxide, and extracted
several times with diethyl ether. The ethereal extracts
were combined, extracted with 300 ml of 6N hydrochloric
acid and 200 ml of water. The aqueous acid extracts
were combined, made alkaline, and then extracted with
X-6172 -13-
fresh diethyl ether. The ethereal extracts were com-
bined, washed with water, dried and concentrated to
give 9.9 g (84.6% yield3 of a white solid. The solid
was dissolved in 100 ml of cold (0-5C) acetone and the
solution was saturated with hydrogen chloride. The
mixture was stirred for forty-five minutes and filtered
to give 8.0 g (77.8%) of 9-carbamoyl-9-(3-isopropyl-
aminopropyl)fluorene hydrochloride. The product was
recrystallized from isopropanol to give 4.7 g (58.7%
yield) of the hydrochloride salt melting at 206-208C.
High pressure liquid chromatography estab-
lished the product to be almost 100% 9-carbamoyl-9-
(3-isopropylaminopropyl)fluorene hydrochloride, with no
detectible amounts of dimer or trimer.
Analysis calculated for C20H25ClN20
Theory: C, 69.65; H, 7.31; N, 8.12
Found: C, 69.90; H, 7.44; N, 8.03.
NMR (DMSOd6): ~ 1.1 (d, 6H); 2.1-3.4 (m, 7H); 6.22
(s, lH); 7.0 (s, lH) 7.4-8.2 (m, 8H); 8.5-9.1 (broad s,
2H)
Example 5
A solution of 10.1 g (38 mM) of 9-carbamoyl-9-
(2-cyanoethyl)fluorene in 190 ml of ethanol and 8.66 g
(76 mM) of trifluoroacetic acid containing 2.0 g of
platinum oxide was shaken for four and one-half hours at
25C under 4 atm. of hydrogen. The reaction mixture was
o~
X-617~ -14-
then added to a mixture of 2.0 g of 5% palladium on
charcoal in 20 ml of ethanol containing 8.34 ml of
acetone and 6.3 g of sodium acetate. This reaction
mixture was shaken for twenty hours at 25C under 4 atm.
of hydrogen. The reaction mixture was filtered and the
filtrate was concentrated to give 32.2 g of a viscous
oil. The oil was added to 200 ml of ice water and the
aqueous mixture was made alkaline by addition of 50%
(w/v) aqueous sodium hydroxide. The aqueous alkaline
mixture was extracted several times with diethyl ether.
The ethereal extracts were combined and extracted with
300 ml of 6N hydrochloric acid and 200 ml of water. The
aqueous acid extracts were combined, made alkaline by
addition of fresh sodium hydroxide, and extracted with
fresh diethyl ether. The ethereal extracts were com-
bined, washed with water, dried and concentrated to
dryness to give 11.1 g ~94.8% yield) of product. The
product was dissolved in 80 ml of acetone and the
solution was saturated with hydrogen chloride to give
10.2 g (91.8%) of white solid. The solid was crystal-
lized from 105 ml of isopropanol to provide 6.8 g
(66.5%) of 9-carbamoyl-9-(3-isopropylaminopropyl)-
fluorene hydrochloride. M.P. 205-208C. High per-
formance liquid chromatography demonstrated that the
product contained no detectable amount of dimer or
trimer. Elemental analysis and NMR were consistent with
those for the products of Examples 3 and 4.
