Note: Descriptions are shown in the official language in which they were submitted.
S~SO
X-5060F~
OCTAHYDRO--2H-PYRROLO [ 3, 4-g ] QUINOLINES
This invention, in one aspect, prcvides trans-dl-5 and
7-substituted-4,4a,5,6,7,8,8a,9-octahydro-2H-
pyrrolo[3,4-g]quinolines of the following structure
R N~2 T T T
1 0 \3~3~4~ S- I
wherein
Rl is H or Cl-C3 alkyl;
R is Cl-C3 alkyl or allyl;
R is H or CH2X wherein X is C~, CONH2,
SO2CH3, SCH3 or OCH3~ and
~ he pharmaceutically-acceptable acid
addition salts thereof.
The compounds of formula I can be prepared
by reacting a compound of the formula
/ \
2s ,I, ,~R2
t
,/
R~ Id
,
~1~5750
)B --2--
wherein
Rl,is (Cl-C3)alkyl-CO;
R ~is H, Cl-C3 alkyl, or allyl;
R is H or CH2Y;
S Y is Cl, Br, OSO2phenyl, O-tosyl, or
- S2(Cl-C3)alkyl;
with base to provide the compounds of
formula I wherein Rl is H;
optionally followëd by reacting with an
alkyl halide to obtain the compounds of formula I
where Rl is Cl-C3 alkyl;
where R is H followed by reacting with an
alkyl or allyl halide or reductive alkylation with an
appropriate aldehyde and metal hydride to obtain the
compounds of formula I where R2 is Cl-C3 alkyl or
allyl;
followed by reacting the compound of
formula Id where R3 is CH2Y with sodium methylate,
methylmercap~ sodium salt, sodium cyanide, or sodium methanesulfinate,
to obtain the o~x~nds of fornLla I where R3 is CH2X where X is,
respectively OCH3, SCH3, CN, or S02CH3; and
opt~lly followed by reacting the o~npounds of formLla I
where R3 is ~ CN with hydration to obtain the o~pounds of formLla I
where R3 is CH2oONH2;and where desired, formmg pharmaceutically
acoq~ble acid addition salts of the om~ounds of fonn~a I.
The compounds of formula I, and the process for
preparing same, are also disclosed and are claimed, in Canadian
Patent Application.330,551, filed June 26, 1979, of which this
application is a divisional.
In the above formula, the ring junction
(the 4a, 8a bond) is trans and the compounds are
obtained as a racemic pair. The two stereoisomers
constituting the racemate can be drawn as structures
Ia and Ib below
.
1~14575(~
X-5060~3 _3_
tsa 7 9~ ~e\~/ \ \R3
Rl-~2 t I and R~ 2 ~ T
\3~3,4~ ~ \3~,~3~4~ ~
Ia - Ib
In addition, introduction of a substituent
at C-7 (R3 is other than H) creats a new chiral
center and the compounds of that structure exist as
4 stereoisomers in two racemic pairs. The synthetic
procedures to be set forth herein yield a single
predominant racemate consisting of the 4a~,7~,8aa
isomer and its mirror image, the 4a~,7~,8a~ isomer.
Resolution of this racemate into its component
diastereoisomers can be readily accomplished by
methods currently available in the art. Regardless
of the structure currently assigned to a given
isomer or racemate, this invention provides com-
pounds of the above formula having dopaminergic
activity, whether in pure form as a single di-
astereoisomer or admixed with one, or more, less
active or even inactive diastereoisomers.
Also within the scope of this invention
are novel intermediates of the formula
1145750
X-5060B --4--
,I, ~I-R~
~I, ,1 IC
R~
wherein
Rl is ~ or (Cl-C3)alkyl-CO;
R2 is H, benzyl or Cl-C3 alkyl; and
R3 is H, COO(Cl-C3)alkyl, COOH, or CH~Xl
wherein Xl is OH, Cl, OSO2(Cl-C3)alkyl, OSO2 tolyl,
or OSO2phenyl; 1 3
with the proviso that both R and R can
not be H when R2 is Cl-C3 alkyl; and
their salts.
In the above formulas, the term "Cl-C3
alkyl" includes methyl, ethyl, n-propyl and iso-
propyl.
The pharmaceutically-acceptahle acid
addition salts of this invention include salts
derived from inorganic acids such as: hydrochloric
acid, nitric acid, phosphoric acid, sulfuric acid,
hydrobromic acid, hydriodic acid, nitrous acid,
phosphoric acid and the like, as well as salts
der~ved from nontoxic organic acids such as ali-
phatic mono and dicarboxylic acids, phenyl-sub-
stituted alkanoic acids, hydroxy alkanoic and
~ ,~
11457SO
X-5060B
alkandioic acids, aromatic acids, aliphatic and
aromatic sulfonic acid. Such pharmaceutically-ac-
ceptable salts thus include sulfate, pyrosulfate,
bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, meta-
phosphate, pyrophosphate, chloride, bromide, iodide,
fluoride, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caprate, heptanoate,
propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, mandelate, butyne-
1,4-dioate, hexyne-1,6-dioate, benzoate, chloro-
benzoate, methylben20ate, dinitrobenzoate, hydroxy-
benzoate, methoxybenzoate, phthalate, terephthalate,
benzenesulfonate, toluenesulfonate, chlorobenzene-
sulfonate, xylenesulfonate, phenylacetate, phenyl-
propionate, ~henylbutyrate, citrate 9 lac~ate, ~-
hydroxybutyrate, glycollate, malate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-
l-sulfonate, naphthalene-2-sulfonate and the like
~alts.
The intermediates coming within the scope
of Fon~a Ic rorm useful salts with all varieties of
acids, not just non-toxic acids, and these salts are
used for reaction and purification purposes.
Illustrative compounds falling within the
scope of formula I include:
trans-dl-2j5-dimethyl-7-methylmercapto-
methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-
glquinoline sulfate
-
7S(~
X-5060B -6-
trans-dl-2,5-dimethyl-7-methoxymethyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline
sulfate
trans-dl-5-methyl-4,4a,5,6,7,8,8a,9-octa-
hydro-2H-pyrrolo[3,4-g]quinoline hydrochloride
trans-dl-5-isopropyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrrolol3,4-g]quinoline
trans-dl-2-methyl-5-n-propyl-7-methyl-
sulfonylmethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-
O pyrrolo[3,4-g]quinoline maleate
trans-dl-5-ethyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrrolo[3,4-g]quinoline
trans-dl-5-allyl-4,4a,5,6,7,8,8a,9-octa-
hydro-2H-pyrrolot3,4-g~quinoline.
. The compounds of fo~mula I in which R3 is
H are prepared according to the procedure outlined
in ~eaction Scheme I below. In Reaction Scheme I,
only one stereoisomer has been drawn for convenience,
but it should be remembered that each decahydro-
quinoline and each octahydropyrrolot3,4-g]quinoline
exists as a racemate. In addition, R2 is other than
H.
, ' 11~57SO
X-5~60r~ -7-
Reaction Scheme I
I~ ' pyrrol idine acrylamide
ac i d cata I ys~ / \ /-
o co z Z-c~I
III H
R2X I NaH
V R2 I z
HC I IV
2 0 NaCNBH3
~ _ \ HzSO- / I~
VI RZ VII RZ
(CHs) 2NCH(OZ ~ ~ ) z
~CHaCO) zO K g l yc i nate O~ / \-/ \
(CHs) 2NC~ H\N/
VIII RZ
.,,
~ ~ '
11~5750
X-50~0Ps --8--
S ',i,,~ `r~
CH3C0 H
IX X
In the above reaction scheme, Z-CO is an acyl pro-
tecting group in which Z i5 (Cl-C3)alkyl, (C2-C3)-
alkenyl, ~C2-C3)alkynyl, (C5-C6)cycloalkyl, phenyl
or.substituted phenyl wherein the substituting group
can be methyl, methoxy, chloro and the like, at any
position of the phenyl ring. Illustratively, Z-CO
can be acetyl, propionyl, butyryl, propiolyl,
acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl, or m-
methoxybenzoyl.
Acetals of dimethylformamide useful in
producing compound VIII in Reaction Scheme I (and
compound XV in Reaction Scheme II below) have the
general formula (CH3)2N-CH-(OZ'')2 in which Z " is
(Cl-C8)alkyl, ~C5 C6)cycloalkyl, (C3-C4)alkenyl,
(C3-C4)alkynyl and the like. We prefer to employ
one of the commercially available acetals of di-
methylformamide; i.e.: the dimethyl, diethyl,diisopropyl, dibutyl, dicyclohexyl, dipropyl or
dineopentyl acetals.
.
11457SO
~-so60n _9_
In accordance with Reaction Scheme I, 4-
acyloxycyclohexanone (II) prepared by the procedure
of E.R.H. Jones and F. Sondheimer, J. Chem. Soc.,
615, (1949) is reacted with pyrrolidine in the
presence of an acid catalyst to yield a pyrrolidine
enamine. This enamine is in turn reacted with
acrylamide to produce a mixture of dl-6-acyloxy-
3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and dl-
6-acyloxy-3,4,4a,5,6,7-hexahydro-2(lH)-quinolinone
represented by formula III, the dotted lines in-
dicating the alternative positions of the double
bond.
Next, the acidic nitrogen (acidic since it
is alpha to a carbonyl group) is alkylated with an
alkyl halide R2X wherein R2 has the same meaning as
hereinabove and X is a halogen such as Cl, Br or I,
in the presence of sodium hydride to yield a mixture
of dl-l-(Cl-C3) alkyl (or allyl or benzyl)-6-
acyloxy-3,4,5,6,7,8-hexahydro-2(lH)-quinolinone and
its ~8 isomer (IV). Reduction of this amide with
lithium aluminum hydride or other suitable organo-
metallic reducing agent yields a mixture of dl-
l-(Cl-C3) alkyl (or allyl or benzyl)-6-hydroxy-
1,2,3,4,5,6,7,8-octahydroquinoline and its ~8
isomer. In this reaction mixture, conditions are
encountered which serve to hydrogenolyze the acyloxy
group to a hydroxyl group at C-6. The dl-l-(Cl-C3)-
alkyl (or allyl or benzyl)-6-hydroxyoctahydroquino-
line mixture i5 next converted to an ammonium salt by
treatment with hydrochloric acid, and the ammonium
. .
- 114S7SO
x-s~. ~or -lo-
salt is then reduced with sodium cyanoborohydride to
yield trans-dl-l- (Cl-C3)alkyl (or allyl or benzyl)-
6-hydroxydecahydroquinoline (VI). Next, the trans-
dl-l- (Cl-C3 alkyl, allyl, or benzyl)-6-hydroxy-
5 decahydro~uinoline ~VI) is oxidized using, preferably,chromium trioxide in acetic acid, to yield the
corresponding 6-oxo compound (VII). By adapting the
procedure o~ Zav'yalof et al. C.A., 80, 59815z(1974),
Izv. Akad. N uk. SSSR. Ser. Khim 2572-7 (1973), this
10 6-oxo compound (VII) is reacted with dimethylform-
amide dimethylacetal to yield a 7-dimethylamino-
methylene-6-oxo-derivative (VIII). Reaction of this
derivative with potassium glycinate followed by
treatment of the thus formed intermediate product
15 with acetic anhydride yields a tricyclic derivative,
trans-dl-2-acetyl-5- [(Cl-C3)alkyl, allyl or benzyl)]-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quino-
line ~IX). Removal of the acetyl group at N-2 with
base yields the dopamine agonist (X) when R2 is
20 ~Cl-C3~alkyl or allyl, or a u~eful intermediate when
R is benzyl.
Those compounds in which Rl is Cl-C3 alkyl
are prepared from compound X by taking advantage of
the acidic hydrogen in the pyrrole ring and reacting
25 an anionic salt thereof, prepared from sodium hydride
or other suitable base, with an alkyl halidP, Rl X
where Rl is (Cl-C3) alkyl or allyl and X is Cl, Br or
Those compounds in which R2 i~ benzyl can
30 be transformed into compounds in which R2 is
~Cl-C3)alkyl or allyl as follows: the benzyl group
11'~5750
X-5060B
--11--
can be removed by reductive cleavage or by treatment
with cyanogen bromide to yield, eventually, a com-
pound in which R2 is H. The usual conditions for
removing an N-benzyl group are hydrogen with a
palladium-on~carbon catalyst or reaction with cyano-
gen bromide followed by reductive (Zn and acetic
acid) cleavage of the N-cyano compound. This
debenzylated compound can then be al~ylated with an
allyl or a lower alkyl halide, or alternatively it
may be reductively alkylated using acetaldehyde,
propionaldehyde or other aldehyde with a metal
hydride, such as sodium cyanoborohydride.
Compounds according to formula I above in
which R3 is other than H are prepared according to a
slightly different, but comparable, synthetic route
illustrated in Reaction Scheme II below. As in
Reaction Scheme I, the synthetic procedure is
illustrated for convenience with respect to a single
stereoisomer (referring to the bridgehead config-
uration) the 4aB,8a~ isomer.
il~5750
~-5060B
--12--
Reaction Scheme II
O
/-\ RZNH2 ~ / \ ~ \t-COOZ~
~ CH2=C-COOZ'
I CH2Hal
O-CO-Z XI R
II - acid
H \ BH4
lo t ~ r , z OH / OH
XIIII R2 \ ~ XII
. pyridine-HCI RZ
CrOs
~ /
/ \-/ \ , (CHs)
0=~ COOZ ~
H IN O= /-\~/-\ COOZ'
XIV R (CH3)2NCH= ~\ /i\N/
XV R2
K glycinate
acetic anhydrTde
\ /
H= / \-/ \t-COOZ'
/ hydrlYSis ACN~cH=~
H~c t T r R2
H \~ XVI
~:, R2
XVII
1145750
~-5060B
-13-
wherein Z and Z'' have the same significance as in
Reaction Scheme I, Hal is chloro or bromo and Z' is
part of a readily hydrolyzable group Z'O-CO including
(Cl-C2)al~yl, phenyl subs-tituted (Cl-C2)alkyl, illus-
tratively benzyl, phenethyl, p-methoxybenzyl, methyl,
ethyl and others.
In accordance with the Reaction Scheme II,
a 4-acyloxycyclohexanone (II) is reacted with an
a-halomethylacrylate ester, for illustrative pur-
poses, the ethyl ester, and an amine, RNH2, wherein Ris Cl-C3 alkyl, allyl or benzyl. The product of this
reaction is a mixture of dl-l-substituted-3-ethoxy-
carbonyl-6-acyloxy-1,2,3,4,5,6,7,8-octahydroquinoline
and dl-l-substituted-3-ethoxycarbonyl-6-acyloxy-
1,2,3,4,4a,5,6,7-octahydroquinoline represented by XI
in which the dotted line indicates the alternate
positions of the double bond. The hydrochloride
salts of these isomers are prepared and the resulting
mixture reduced with sodium cyanoborohydride to yield
trans-dl-1-substitu~ed-3-ethoxycarbonyl-6-acyloxy-
decahydroquinoline (XII). Hydrolysis of this diester
to yield a 6-hydroxy-3-carboxylic acid followed by
reesterification of the carboxylic acid group with
ethanol or other alcohol in the presence of acid
yields trans-dl-1-substituted-3-e~hoxycarbonyl-6-
hydroxydecahydroquinoline txIII). Oxidation of the
hydroxy group with Sarett's Reagent (pyridine hydro-
chloride and chromium trioxide) produces the cor-
responding 6-oxo compound (XIV). Treatment of this
6-oxo derivative with dimethylform~mide dimethyl-
11457SO
X-5060s
-14-
acetal results in reaction at C-7 (adjacent to the
keto group) to give trans-dl-l-substituted-3-ethoxy-
carbonyl-6-oxo-7-(dimethylaminomethylene)decahydro-
quinoline (XV). Reaction of this derivative with
potassium glycinate followed by a treatment of the
intermediate product with acetic anhydride gives the
tricyclic derivative, trans-dl-2-acetyl-5-substi-
tuted-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-
2H-pyrrolo~3,4-g]quinoline (XVI). Hydrolysis with
sodium ethoxide in ethanol yields the NH compound
(XVII).
The octahydropyrrolo[3,4-g]quinoline of
Formula XVI represents a single isomer. The mirror
image of XVI is produced concomitantly and is in-
cluded within the scope of this invention. Webelieve, based upon analogy with the D-ergolines,
that the diastereoisomer XVI as drawn is the isomer
having dopamine ~gonist activity. The trans-dl
racemate, which contains XVI and its mirror image, is
of course useful as a dopamine agonist, even though
most of the desired activi~y resides in one of its
component stereoisomers.
Compounds according to XVI above in which
R2 is methyl or benzyl can be transformed into
compounds in which R2 is ethyl, allyl or n-propyl by
reaction with cyanogen bromide. The intermediate
5-cyano derivative can be reductively cleaved (zinc
plus acetic acid) to yield a compound in which R2 is
H. In addition, the benzyl group can be removed by
hydrogenation with palladium-on-carbon to yield those
5750
X--5 0 6 0 B
--15--
intermediates in which R2=H. Alkylation of those
compounds in which R2 is H can be accomplished by
reaction with an alkyl halide, R2Cl, R2Br or R2I.
Alternatively, the secondary amine can be reacted
with acetadehyde, acrolein, or propionaldehyde under
reducing conditions (NaBH3CN) to yield an N-ethyl,
N-allyl or N-n-propyl derivative.
The dopamine agonists of formula I in
which R3 is other than H; i.e. those compounds in
which R3 is CH2X wherein X is CN, OCH3, SCH3,
SO2CH3 or CO;NH2, are prepared according to Reaction
Scheme III helow
' , ' ' ' ,', ' '
.
- ; .
.~ .
li45750
x-50~0r~
--16--
Reaction Scheme III
CH~r COOZ '
LiAlH4 XVII
\ /
1 o f
tosy l-C I SOC I 2
(Cl -Cs) a I ky I -SO2C I PC 15
pheny I -SO~C I POC i 3
PBr3
\ /
CH ~ \Nr
XIX
NaCN
2 5 CHsSNa
CH~ONa
\ CHsSO~Na
CH ~ \N/r
R
57SO
X-5060~
-17-
wherein Z' and R have the same significance as
before, Y is a "leaving" group: Cl, Br, OSO2phenyl,
O-tosyl or SO2(Cl-C3)alkyl, R2 is H, SO2phenyl, tosyl
or SO2tCl-C3)alkyl, and X is CN, SCH3, OCH3 or
SO2C~3. The acetyl group of a compound according to
XVI in Reaction Scheme II is hydrolyzed with sodium
ethoxide in ethanol or sodium methoxide in methanol
to yield a desacetyl derivative. The carboalkoxy
group is then reduced with a metal hydride such as
LiAlH4 to an hydroxymethyl group, thus providing a
trans-dl-5-substituted-7-hydroxymethyl-4,4a,5,6,-
7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline
(XVIII). The hydroxyl can be replaced with a chlorine
or bromine lea~ing group and the resulting chloro-
methyl or bromomethyl compound reacted with NaCN toyield a compound in which R3 is C~2-CN. Other
leaving groups--groups readily replaced by a
nucleophilic reagent--such as the mesyloxy, p-
tosyloxy, benzenesulfonyloxy and the like groups
lwhen X in formula I, Ia or Ib or Y in formula
XIX, is OSO2~Cl-C3)alkyl, OSO2phenyl or OSO2tolyl]
can be produced by acylation of the hydroxy group
with a sulfonyl halide. Reaction of the thus-
produced compound with sodium methylate, methyl-
mercaptan sodium salt, sodium cyanide, sodiummethanesulfinate or other basic salts of methanol,
methylmercaptan yields compounds according to
formula I, Ia or Ib in which ~3 is CH2X and X is
SCH3, OCH3, CN or SO2CH3. Compound~s in which X is
CONH2 are prepared by hydration of the corresponding
cyano compound.
11~5750
X-5060B
--18--
Compounds represented by formulas I, Ia and
Ib, in which R2 is H and by form~las IX, and X above
have two centers of asymmetry, the ring junction
carbons at 8a and 4a. Thus, the compounds can occur
as two racemates, ordinarily denominated as the
trans-dl racemate and the cis-dl racemate. It is
believed, however, according to the best evidence
from 13C NMR spectral data of the maleate salt of the
compound according to Formula X above wherein R2 is
benzyl, that the cyanoborohydride reduction (going
from V to VI in Reaction Scheme I) yields a trans-
fused decahydroquinoline. While the arguments for
the trans configuration based upon 13C NMR spectral
data are compelling, an X-ray crystallographic
investigation has also been carried out on the nicely
crystalline enaminoketone (VIII) in which R2 is
methyl, the precursor of the pyrrole (X). This
X-ray analysis indicated clearly that the ring
junction is trans. Thus, only the trans racemate is
prepared by the synthetic procedures disclosed herein
and the compounds of formula I are preferably
represented as the trans-dl steroisomers Ia and Ib
above in which R3 is H. Resolution of this racemate
into its optical antipodes can be accomplished by
procedures known to those skilled in the art, and
the individual trans-d and trans-l isomers are
included within the scope of this invention.
When R3 is other than H, a third chiral
center is introduced at C-7, thereby doubling, at
least in theory, the number of isomers produced by
575(~
X-5060B
--19--
Reaction Schemes II and III. However, it is pres-
ently believed that the configuration of the C-7
group is "trans" to that of the 8a hydrogen. Thus
in Ia above, R3 when it is other than H, has a beta
configuration with the Ba hydrogen having an alpha
configuration. In the mirror image Ib, the 8a
hydrogen is beta and the C-7 substituent alpha.
Thus the dl-trans-7-subYtituted octahydropyrrolo-
[3,4-g]quinolines of formula I are provided sub-
stantially as a single racemate.
In addition, it is apparent from an in-
spection of the dl-trans-l(substituted)-6-keto
decahydroquinoline (VII) that reaction with di-
methylformamide dimethylacetal could take place at
either C-5 or C-7 since both these carbons are ortho
to the ketone group and are thus "activated". The
same X-ray crystallographic analysis of the enamine
(VIII) clearly indicated that reaction had taken
place at C-7 rather than C-5. ~ence, the final
tricyclic compounds IX, X, XVI and I are the linear
pyrrolo[3,4-g]quinolines rather than the angular
tricyclic compounds (which would be named as 4,4a,-
5,6,7,8,8a,9-octahydro-1~-pyrrolo[2,3-i]quinolines).
This invention is further illustrated by
the following specific examples.
1145 ;J50
~-50~0B
-20-
STARTING MAmERIALS
Example A
Preparation of trans-dl-2-Acetyl 5-methyl-
4,4a,5, 6,7,8,8a,9-octahydro-2H-pyrrold B,4-g]quino-
line.
A reaction mixture was prepared from 52 g.
of 4-benzoyloxycyclohexanone, 30 ml. of pyrrolidine,
a few crystals of p-toluene sulfonic acid mono-
hydrate, and 1000 ml. of benzene. The reaction
mixture was heated to refluxing temperature under a
nitrogen atmosphere for one hour in an apparatus
equipped with a Dean-Stark water trap. ~he reaction
mixture was then cooled and the solvent and other
~olatile materials removed by evaporation in vacuo.
The residue, comprising the pyrrolidine enamine of
4-benzoyloxycyclohexanone formed in the above re-
action was dissolved without further purification in
1000 ml. of dioxane. 42.6 g. of acrylamide were
added. ~his new reaction mixture was heated under a
nitrogen atmosphere at reflux temperature for
twenty-one hours. Thin-layer chromatography of the
reaction mixture indicated one major spot. The
reaction mixture was cooled and the volatile con-
stituents removed by evaporation in vacuo. Achloroform solution of the residue comprising 6-
benzoyloxy-3,4,5,6,7,8-hexahydro-lH-quinolin-2~one
and the isomeric product 6-benzoyloxy-3,4,4a,5,-
6,7-hexahydro-lH-quinolin-2-one was chroma~ographed
over 350 g. of"Flrisil"* using chloroform containing
* Trademark for a hard, porous, granular activated magnesium
silicate, used in chromatography.
11'.~s5750
X-5060B
-21-
increasing quantities of ethanol (0 to 2 percent) as
the eluant. Fractions found to contain 6-benzoyl-
oxy-3,4,5,6,7,8-hexahydro-lH-quinolin-2-one and its
isomer by thin-layer chromatography were combined
and the solvent removed therefrom in vacuo. The re-
sulting residue was crystallized by triturating with
hexane to yield a crystalline mixture of 6-benzoyl-
oxy-3,4,5,6,7,8-hexahydro-lH-quinolin-2-one and the
corresponding 3,4,4a,5,6,7-hexahydro derivative.
The mixture melted in the range 130-150C. after
recrystallization from an ether-hexane solvent
mixture.
Analysis: Calculated: C, 70.83; H, 6.32;
N, 5.16;
Found: C, 71.05; H, 6.19,
N, 5.33.
NMR of the product isolated above in-
dicated that the mixture contained about 60 percent
24 of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-lH-quino-
lin-2-one and 40% of the 3,4,4a,5,6,7-hexahydro
isomer.
46.5 g. of the above isomer mixture were
dissolved in 400 ml. of tetrahydrofuran (THF).
80 ml. of methyl iodide were added and the resulting
mixture cooled in an ice-water bath. 9.6 g. of
sodium hydride (as a 50 percent suspension in
mineral oil) were added in portions. After all of
the sodium hydride suspension had been added, the
cooling bath was removed and the reaction mixture
:
ll~S7~0
X-5060s
--22-
stirred at ambient temperature under a nitrogen
atmosphere for about 4 hours. The reaction mixture
was then diluted with water and the aqueous mixture
thoroughly extracted with chloroform. The chloro-
form extracts were combined and the combinedextracts washed with saturated aqueous sodium
chloride and dried. The chloroform was removed by
evaporation to dryness in vacuo leaving as a residue
an orange oil weighing 47.3 g. Recrystallization
from an e~her-hexane solvent mixture yielded
crystals of l-methyl-6-benzoyloxy-3,4,5,6,7,8-
hexahydro-2(lH)-quinolinone and the corresponding
3,4,4a,5,6,7-hexahydro isomer.
Analysis: Calculated: C, 71.56; H, 6.71; N, 4.91;
Found: C, 71.33; H, 6.90; N~ 4.67.
Following the above procedure, 59 g. of a
mixture of Ç-benzoyloxy-3,4,5,6,7,8-hexahydro-
2(lH)-quinolinone and 6-benzoyloxy-3,4,4a,5,6,-
7-hexahydro-2~lH)-quinolinone were reacted with
n-propyl iodide in the presence of sodium hydride to
yield l-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexa-
hydro-2(lH~-quinolinone and the corresponding
3,4,4a,5,6,7-hexahydro isomer. The compounds were
purified by chromatography over "Florisil~l using an
ether-chloroform solvent mixture as the eluant.
Also following the above procedure, a mixture of the
l-benzyl-6~benzoyloxyhexahydro-2(lH)-quinolinones
was prepared by substituting benzyl bromide for
methyl iodide.
ll~S7SO`
-5060B
--23--
A solution of 47.3 g. of a mixture of 1-
methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro- 2 (lH) -
quinolinone and the corresponding 3,4,4a,5,6,7-
hexahydro isomer as obtained above were dissolved in
800 ml. of THF and the solution cooled to about 0C.
20 g. of lithium aluminum hydride were added thereto
in portions and the resulting mixture refluxed for
four hours under a nitrogen atmosphere. The reaction
mixture was cooled and excess lithium aluminum
hydride destroyed by the addition of ethyl acetate.
10~ sodium hydroxide was then added and the mixture
diluted with water to decompose any organometallics
- present. The aqueous mixture was extracted several
times with a chloroform-isopropanol solvent mixture.
The organic extracts were combined and the combined
extracts washed with saturated aqueous sodium
chloride and then dried. Evaporation of the solvent
yielded as a residue a mixture of the enamines--
l-methyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquino-
line and 1-methyl-6-hydroxy-1,2,3,4,4a,5,6,7-
octahydroqu$nol~ne--formed in the above reaction.
(The lithium aluminum hydride reduction served to
remove the benzoyl group at C-6 as a benzyl alcohol
moiety, leaving a free hydroxyl in that position of
the ring). The above residue, without further
purification, was dissolved in about 300 ml. of
ether and the ethereal solution saturated with
gaseous hydrogen chloride, thus forming the hydro-
chloride salt of the enamine mixture. The ether was
removed by decantation and the residue dissolved in
.
,
X- 5 0 6 OB
-24
a mixture of 200 ml. of THF and 50 ml. of methanol.
This solution was cooled in an ice water bath. 12
g. of sodium cyanoborohydride were added with
cooling and stirring. After all of the cyano-
borohydride had been added, the reaction mixture wasstirred for another 60 minutes and then poured over
a mixture of ice and lN aqueous hydrochloric acid.
The acidic aqueous solution was extracted with
chloroform and the chloroform extract discarded.
The solution was then made basic with 14N aqueous
ammonium hydroxide. Trans-dl-l-methyl-6-hydroxy-
decahydroquinoline formed in the above reaction,
being insoluble in the alkaline medium, separated
and was extracted several times with a chloroform-
isopropanol solvent mixture. The combined extracts
were washed with saturated aqueous sodium chloride
and then dried. Evaporation of the solvent yielded
15 g. of trans-dl-1-methyl-6-hydroxydecahydroquino-
line.
Following the above sequence of reactions,
a mixtùre of l-n-propyl-6-benzoyloxy-3,4,5,6,7,8-
hexahydro-2(1H)-quinolinone and the corresponding
3,4,4a,5,6,7-hexahydro isomer were first reduced
with lithium aluminum hydride to yield a mixture of
~4a and ~8 1-n-propyl-6-hydroxyoctahydroquinolines
which was converted by treatment with ethereal
hydrogen chloride to the enamine hydrochloride.
Reduction of this intermediate enamine hydrochloride
with sodium cyanoborohydride yielded trans-dl-
1-n-propyl-6-hydroxydecahydroquinoline (56 g. of
57SO
-5060B
-25-
starting material yielded 30 g. of product). Also
following the above proceduxe, l-benzyl-6-benzoyl-
oxy-3,4,5,6,7,8-hexahydro-2(lH)-quinolinone in
admixture with l-benzyl-6-benzoyloxy-3,4,4a,5,-
6,7-h~xahydro-2(lH)-quinolinone was reduced with
lithium aluminum hydride to yield the corresponding
l-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquino-
line and l-benzyl-6-hydroxy-1,2,3,4,4a,5,6,7-
octahydroquinoline as a mixture, treatment of which
with ethereal hydrogen hydrochloride yielded the
enamine salt. Reduction of the enamine salt with
sodium cyanoborohydride gave 1-benzyl-6-hydroxydeca-
hydroquinoline (65 g. of starting mixture yielded
49.6 g. of final product).
Fifteen grams of trans-dl-l-methyl-6-
hydroxydecahydroquinoline were dissolved in 250 ml.
of 6N aqueous sulfuric acid. The solution was
cooled in an ice-water bath. A solution of 9 g. of
chromium trioxide in 60 ml. of 6N aqueous sulfuric
acid were added thereto with stirring in dropwise
fashion over a 10-minute period. The cooling bath
was removed and the reaction mixture stirred for an
additional 60 minutes at ambient temperature. The
excess oxidizing agent was decomposed by adding
isopropanol to the reaction mixture. The reaction
mixture was next poured over ice and the acidic
aqueous olution made basic with 14N aqueous
ammonium hydroxide. trans-dl-l-Methyl-6-oxodeca-
hydroquinoline thus formed, being insoluble in the
alkaline layer, separated and was extracted several
~s~so
X-5060B
-26-
times with a mixture of chloroform and isopropanol.
The extracts were combined and the combined extracts
washed wi~h saturated aqueous sodium chloride and
then dried. Evaporation of the solvent in vacuo
yielded trans-dl-l~methyl-6-oxodecahydroquinoline
boiling in the range 105-116C. at 6 torr; yield =
7.7 g. (45%).
Following the above procedure, 29.5 g. of
trans-dl-l-n-propyl-6-hydroxydecahydroquinoline were
dissolved in 300 ml. of glacial acetic acid to which
was added 8 ml. of 18N aqueous sulfuric acid.
55 ml. of a solution of 26.7 g. of chromium trioxide
in 23 ml. of 18M sulfuric acid were added in drop-
wise fashion. trans-dl-1-n-Propyl-6-oxodecahydro-
quinoline formed in the above reaction was isolatedby the above proceduxe; yield = 21.4 g. Still
following the above procedure, 49.6 g. of trans-
dl-l-benzyl-6-hydroxy-decahydroquinoline were
oxidized with chromium trioxide in sulfuric acid to
yield trans-dl-1-benzyl-6-oxodecahydroquinoline;
yield = 21.1 g. of a dark oil.
A reaction mixture was prepared from
7.7 g. of trans-dl-1-methyl-6-oxodecahydroquinoline,
36 g~ of the dimethyl acetal of dimethylformamide
and 250 ml. of benzene. 3enzene was removed by
distillation at atmospheric pressure under nitrogen
until about 1/2 the original volume remained (1.25
hours). Sufficient benzene was then added to make
up the volume to the original volume and the process
was repeated (four times). All of the benzene was
- 5 0 6 OB 11~5750
--27--
finally removed by evaporation in vacuo and the
resulting residue dissolved in 100 g. of dimethyl-
formamide dimethylacetal. This solution was heated
to refluxing temperature under nitrogen for 20
hours. The reaction mixture was then evaporated in
vacuo and a chloroform solution of the residue
chromatographed over lS0 g. of nFlorisil" using as
the eluant, methylene dichloride containing in-
creasing amounts (1-5%) of methanol. Fractions
containing similar compounds as shown by TLC were
combined. The third substance to come off the
column was a yellow solid (wt = 3 g.) The solid was
heated with 100 ml. of ether and the resulting
solution filtered. Concentration of the filtrate to
about 50 ml. yielded 590 mg. of trans-dl-l-methyl-
6-oxo-7-dimethylaminomethylenedecahydroquinoline
melting at 107-109C.
Analysis: Calculated: C, 70.23; H, 9.97; N, 12.60;
Found: C, 70.17; H, 9.74; N, 12.87.
The above reaction was repeated except
that trans-dl-l-n-propyl-6-oxodecahydroquinoline was
used as a starting material and the product was
chromatographed over Florisil" using chloroform
containing increasing quantities of methanol ~1-5%)
as the eluant. trans-dl-l-n-Propyl-6-oxo-7-
dimethylaminomethylenedecahydroquinoline was ob-
tained.
Following the above procedure, trans-
dl-1-benzyl-6-oxodecahydroquinoline was reacted with
dimethylformamide dimethylacetal to yield trans-
" ~ 1
11~575V
x-50~0~
-28-
dl-l-benzyl-6-oxo-7-dimethylaminomethylenedecahydro-
quinoline melting at 109-111C. after recrystal-
lization from an ether-hexane solvent mixture.
Analysis: Calculated: C, 76.47; H, 8.78; N, 9.29;
Found: C, 76.25; H, 8.66; N, 9.36.
The potassium salt of~glycine was prepared
by reacting 975 mg. of glycine with 730 mg. of
potassium hydroxide in 100 ml. of anhydrous ethanol.
2.~ g. of trans-dl-1-methyl-6-oxo-7-dimethylamino-
methylenedecahydroquinoline were added and the
resulting mixture heated at reflux temperature under
nitrogen for about 3 hours. The reaction mixture
was cooled, the volatile constituents removed in
vacuo and the residue diluted with ether. The
resulting mixture was filtered and the adduct
weighed 3.5 g. The glycine adduct was then cyclized,
decarboxylated and acetylated by heating with
100 ml. of acetic anhydride at reflux temperature
under nitrogen for about 45 minutes. The acetyla-
tion mixture was cooled and the volatile constituents
removed by evaporation to dryness~ The residue,
compri~ing trans-dl-2-acetyl-5-methyl-4,4a,5,6,-
7,8,8a,9-octahydro-2H-pyrrolo~3,4-g]quinoline was
suspended in methylene dichloride and the suspension
filtered to yield 1.7 g. of solid. The methylene
~ichloride filtrate was chromatographed over 150 g.
of "Florisil" using methylene dichloride containing
increasing (0-5%) amounts of methanol as the eluant.
Fra~tions shown by TLC to contain the same substance
1145750
-29-
X-5060s
were combined, and the combined fractions washed
with sodium bicarbonate and saturated aqueous sodium
chloride and then dried. Evaporation of the solvent
in vacuo yielded a residue which was rechromatographed
over 30 g. of Floris~ usin~ chloroform containing
5% methanol as the eluant. Fractions shown by TLC
to contain the same substance were combined to yield
1.72 g. of a viscous orangé oil comprising purified
trans-dl-2-acetyl-5-methyl-4,4a,5,6,7,8,8a,9-octa-
hydro-2H-pyrrolo[3,4-g~quinoline. The orange oil
was dissolved in ether and a solution of 870 mg. of
maleic acid in ether added thereto. The maleate
salt thus formed melted at 201-203C. after re-
crystallization from methanol ether solvent mixture
(1:2).
Analysis: Calculated: C, 62.05; H, 6.94; N, 8.04;
Found; C, 61.81; H, 6.82; N, 1.97.
Following the above procedure, trans-dl-
2-acetyl-S-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-
2~-pyrrolo~3,4-g]quinoline was prepared from trans-
dl-2-n-propyl-6-oxo-7-dimethylaminomethylenedeca-
hydroquinoline by reaction with the potassium salt
of glycine followed by acetic anhydride. The
compound was purified by chromatography.
Following the above procedure, trans-dl-
l-benzyl-6-oxo-7-dimethylaminomethylenedecahydro-
quinoline was reacted with the potassium salt of
glycine and acetic anhydride to yield trans-dl-
2-acetyl-5-benzyl-4,4a,5,6,7,8,8a,9-octahydro-2H-
pyrrolo[3,4-g3quinoline. This latter derivative was
~l~S7SO
-30-
X-5060B
purified by chromatography over Florisil n and then
converted to the maleate salt. Trans-dl-2-acetyl-
5-benzyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-
g]quinoline maleate melted at 162-164C. after
recrystallization from a methanol-ether solvent
mixture.
Analysis: calc.: C, 67.91; H, 6.65; N, 6.60;
Found : C, 67.76; H, 6.40; N, 6.58.
Example B
Preparation of trans-dl-2-Acetyl-5-n-Propyl-4,4a,-
5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
A solution was prepared from 2.5 g. of
trans-dl-2-acetyl-5-benzyl-4,4a,5,6,7,8,8a,9-octa-
hydro-2H-pyrrolo[3,4-g]quinoline and 200 ml. of
methylene dichloride. 4 g. of cyanogenbromide were
added and the resulting mixture was stirred at
ambient temperature under a nitrogen atmosphere for
about 16 hours. Volatile constituents were removed
by evaporation in vacuo. A chloroform solution of
the residue containing trans-dl-l-acetyl-S-cyano~
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quino-
line formed in the above reaction was chromato-
graphed over 200 g. of "Florisil~ using chloroform as
the eluant. Fractions shown to contain the desired
compound were combined and the solvent removed
therefrom. Recrystallization of the residue from
ether yielded crystalline tran~-dl-2-acetyl-
5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-
1145~75'0
X--5060R
[3,4-g]quinoline melting at 135-7C. (total yield =
630 mg.)
A mixture of 0.6 g. of trans-dl-2-
acetyl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H
pyrrolo[3,4-g]quinoline, 50 ml. of glacial acetic
acid, 10 ml. of water and 3 g. zinc dust was heated
at refluxing temperature under a nitrogen atmosphere
for about 7 hours. The reaction mixture was then
filtered and the filtrate poured over ice. The
aqueous filtrate was then made basic with 14N
aqueous ammonium hydroxide. The aqueous alkaline
layer was extracted several times with a mixture of
chloroform and isopropanol. The organic extracts
were combined and the combined extracts washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the solvent in vacuo yielded a
residue which was shown to be one-spot material by
TLC. The residue was dissolved in 50 ml. of di-
methylformamide to which was added 0.~ g. potassium
carbonate and 0.4 ml. of n-propyl iodide. This
reaction mixture was stirred at ambient temperature
under a nitrogen atmosphere for about 16 hours. The
reaction mixture was then diluted with water and the
diluted mixture extracted with ethyl acetate. The
ethyl acetate extract was washed with water and
saturated aqueous sodium chloride and then dried.
Evaporation of the solvent in vacuo yielded a
residue shown to contain one major spot by TLC of
the productO trans-2-acetyl-5-n-propyl-4,4a,5,6,7,-
8,8a,9-octahydro-2H-pyrrolol3,4-glquinoline.
1145'750
-32-
X-5060B
Exam~le C
Preparation of trans-dl-2-Acetyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrrolo~3,4-g]quinoline.
3.5 Grams of trans-dl-2-acetyl-5-benzyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quino-
line were dissolved in 196 ml. of ethanol to which
solution was added O.S g. of a 5% palladium-
on-carbon catalyst. The mixture was hydrogenated in
an Adams machine at room temperature at an initial
hydrogen pressure of 4.13 x 106 dynes/cm.2. After 2
hours, lO0~ of the theoretical amount of hydrogen
had been absorbed. The hydrogenation mixture was
removed from the machine and the catalyst separated
lS by filtration. TLC indicated that there were two
major spots, one being starting material. The
filtrate was concentrated in vacuo to yield crys-
talline material. Concentration of the filtrate
yielded a further batch of crystalline material.
These two batches were combined, dissolved in water
and the aqueous solution made basic with 14N aqueous
ammonium hydroxide. The alkaline layer was ex-
tracted several times with a mixture of chloroform
and isopropanol. The organic extracts were combined
and the combined extracts were washed with saturated
aqueouC sodium chloride and dried. Evaporation of
~he solvent yielded a residue comprising trans-
dl-2-acetyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-
13,4-g]~uinoline formed in the above hydrogenation.
The residue was washed with hexane. It melted at
1145750 ` .
X-5060B
-33-
89-91C. The maleate salt was prepared by dis-
solving the residue in ether and adding an excess of
maleic acid in ether. The maleate salt was re-
crystallized from a mixture of methanol and ether
S and melted at 150-1C.
Example D
Preparation of trans-dl-4,4a,5,6,7,8,8a,9-Octa-
hydro-2H-pyrrolol3,4-glquinoline.
Three-tenths grams of trans-dl-2-acetyl-
4,4a,S,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]-
quinoline were dissolved in lS ml. methanol to which
was added 2 ml. of 2N aqueous sodium hydroxide. The
hydrolysis mixture was stirred at ambient tempera-
lS ture under nitrogen for 3/4 hour. The reaction
mixture was then diluted with water and the alkaline
layer extracted with a mixture of chloroform and
isopropanol. The organic extract was separated,
washed with saturated aqueous sodium chloride and
then dried. Evaporation of the solvent yielded a
residue showinq a sinqle spot by TLC. The residue
was dissolved in ether and an excess of an ethereal
solution of maleic acid added thereto. The re-
sulting gummy precipitate was separated, dissolved
in methanol, and the methanol solution diluted with
ether to yield crystalline material. tranq-dl-
4,4a,5,6,7,8,8a,9-Octahydro-2H-pyrrolo[3,4-g]quino-
line maleate thus prepared melted at 190C. with
decomposit~on.
.
~: . . ~ . . . .
' : ' . . :
- ~ ~
S750
X-50~0B
--34--
Example E
Preparation of l-n-Propyl-6-benzoyloxy-3,4,5,6,7,8-
hexahydro-2(lH)-quinolinone and l-n-Propyl-6-
benzoyloxy-3,4,4a,5,6,7-hexahydro-2(lH)-quinolinone
A reaction mixture was prepared containing
4.4 g. of 4-benzoyloxycyclohexanone [prepared by the
procedure of E. R. H. Jones and F. Sondheimer, J.
Chem. Soc., 615 (1949)], 2.5 ml. of n-propylamine
and 100 ml. toluene. The mixture was heated to
reflux temperature in a nitrogen atmosphere using a
Dean Stark water trap for about 2 hours. The
reaction mixture was then heated to refluxing
temperature for an additional 2 hours in the
presence of a molecular sieve to remove water. The
reaction mixture was then cooled and the solvent
removed by evaporation in vacuo. 4 ml. of methyl
acrylate and 100 ml. of dioxane were added to the
residue which was then refluxed overnight under a
nitrogen atmosphere. The reaction mixture was again
cooled and the volatile constituents removed by
evaporation in va¢uo. Chromatography of an ethereal
solution of the resulting residue over 200 g. of
"Florisil" using ether as an eluant yielded a mixture
of 1-n-propyl-6-henzoyloxy-3,4,5,6,7,8-hexahydro-
2tlH)-quinolinone and l-n-propyl-6-benzoyloxy-
3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone: yield =
2.15 g.
X - 5 0 6 0 B :1145750
Example F
Preparation of trans-dl-2-Acetyl-5-n-propyl-7-
ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-
[3,4-g]quinoline
A mixture of 10 ml. of n-propyl amine and
400 ml. of toluene were cooled in an ice-water bath.
A solution of 16.5 g. of ethyl a-(bromomethyl)-
acrylate in 50 ml. of toluene was added thereto in
dropwise fashion. The resulting mixture was stirred
with cooling for about 25 minutes. Next, a solution
of 11 g. of 4-benzoyloxycyclohexanone in 75 ml. of
toluene was added in dropwise fashion. This new
mixture was heated under a nitrogen atmosphere to
refluxing temperature for about 23 hours. The
reflux condenser was equipped with a Soxhlet
extractor containing a 5A sieve to remove water.
Next the rea~tion mixture was cooled and the cooled
mixture filtered. Evaporation of the filtrate
yielded a residue comprising a mixture of l-n-
propyl-3-ethoxycarbonyl-6-benzoyloxy-1,2,3,4,5,-
6,7,8-octahydroquinoline and 1-n-propyl-3-ethoxy-
carbonyl-6-benzoyloxy-1,2,3,4,4a,5,~,7-octahydro-
quinoline. The residue was dissolved in an ether-
chloroform solvent mixture and the resultingsolution saturated with gaseous hydrogen chloride
while maintaining the temperatuxe in the range
0-5C. The solve~t was decanted from the crys-
talline hydrochloride salts thus formed. The salts
3~ were dissolved in 100 ml. of methanol. 300 ml. of
,
11~5750
X-5060B
--36--
THF were added and the resulting solution cooled in
an ice-water bath. 15 g. o sodium cyanoborohydride
were added in portions to the stirred and cooled
reaction mixture. After the addition had been
completed, the reaction mixture was stirred for
another 1.25 hours after which time it was diluted
with aqueous sodium bicaxbonate. The aqueous
alkaline mixture was extracted several times with
ethyl acetate. The ethyl acetate extracts were
combined and the combined extracts washed with
saturated aqueous sodium chloride solution and then
dried. Evaporation of the solvent yielded trans-
dl-l-n-propyl-3-ethoxycarbonyl-6-benzoyloxydeca-
hydroquinoline. The compound was dissolved in a
mixture of 400 ml. of methanol and 100 ml. of 2N
aqueous sodium hydroxide. This mixture was stirred
at ambient temperature under a nitrogen atmosphere
for 64 hours after which time the volatile con-
stituents were removed by evaporation in vacuo. The
re~ulting residue was suspended in 800 ml. of
ethanol and 15 ml. of 12N aqueous hydrochloric acid.
The esterification mixture was heated to refluxing
temperature and about 300 ml. of solvent removed by
distillation. 300 ml. of additional ethanol were
added and the reaction mix~ure heated to refluxing
temperature for 26 hours in an apparatus equipped
with a Soxhlet trap containing a 3A sieve. The
reaction mixture was cooled, diluted with aqueous
sodium bicarbonate and the alkaline mixture ex-
tracted several times with chloroform. The chloro-
11~5750
X-5060B
--37--
form extracts were combined and the combined ex-
tracts washed with saturated aqueous sodium chloride
and then dried. Evaporation of the chloroform
yielded 10.3 g. of a residue which was purifled by
chromatography over 150 g. of "Florisil~ using
chloroform containing increasing (2-10%) of methanol
as the eluant. Trans-dl-l-n-propyl-3-ethoxycar-
bonyl-6-hydroxydecahydroquinoline formed in the
above reaction was obtained from the eluate frac-
tions as a purified product.
A solution was prepared from 8.8 g. oftrans-dl-l-n-propyl-3-ethoxycarbonyl-6-hydroxydeca-
hydroquinoline and 400 ml. of methylene dichloride.
41 g. of sodium acetate were added. Next, 10.8 g.
o pyridine hydrochloride:chromium trioxide were
added and the resulting mixture stirred for about 22
hours. The reaction mixture was filtered and the
iltrate concentrated in vacuo. The resulting
concentrate was dissolved in chloroform and the
chloroform solution chromatographed over 150 g. of
"Florisill~using chloroform containing increasing
amounts (1-2%) of methanol as the eluant. Fractions
shown by thin-layer chromatography to contain
tran3-dl-l-n-propyl-3-ethoxycarbonyl-6-oxodeca-
hydroquinoline formed in the above reaction werecombined and the solvent removed from the combined
extracts to yield 3.48 g. of the 6-oxo compound as a
residue. The 6-oxo compound was dissolved in 100
ml. of toluene containing an added 25 ml. of the
dimethylacetal of dimethylformamide. The resulting
~1145750
~-50~0~
-38-
mixture was heated to refluxing temperature under a
nitrogen atmosphere for 44 hours and was then
allowed to remain at room temperature for an
additional 4 days. Volatile constituents were
S removed by evaporation in vacuo and the residue,
comprising trans-dl-l-n-propyl-3-ethoxycarbonyl-
6-oxo-7-(dimethylaminomethylene)decahydroquinoline
formed in the above reaction, was purified ~y
chromatographing a chloroform solution of the
compound ov~er '~Florlsil~ using chloroform containing
increasing amounts (2-5%) of methanol as the eluant.
Fractions shown by TLC to contain the desired 7-
dimethylaminomethylene compound were combined and
the solvent evaporated therefrom in vacuo.
The potassium salt of glycine was prepared
by reacting 280 mg. of potassium hydroxide with
370 mg. of glycine in 50 ml. of anhydrous ethanol.
1.3 g. of trans-dl-l-n-propyl-3-ethoxycarbonyl-
6-oxo-7-(dimethylaminomethylene)decahydroguinoline
were added and the resulting mixture heated under a
nitrogen atmosphere to reflux temperature for about
3 hours. The reaction mixture was cooled and the
volatile constituents removed by evaporation in
vacuo. 50 ml. of acetic anhydride were added to
this residue and the resulting mixture heated to
reflux temperature under a nitrogen atmosphere for
about 45 minutes thus cyclizing, decarboxylating and
acetylating all in one step. Again/ the reaction
mixture was cooled and the volatile constituents
removed by evaporation. In this instance, the
1145750
X-5060s
-39-
residue was next diluted with aqueous sodium bi-
carbonate and the resulting alkaline aqueous layer
extracted with chloroform. The chloroform extract
was separated and the separated extract washed with
saturated aqueous sodium becarbonate and then dried.
~vaporation of the chloroform yielded a residue
which was chromatographed over 35 g. of "Florisil"
using chloroform containing increasing amounts
(0-1%) of methanol as the eluant. Fractions shown
by TLC to contain the desired trans-dl-2-acetyl-
5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-
octahydropyrrolo~3,4-g]quinoline formed in the above
reaction were combined. The solvent was removed
from the combined fractions by evaporation and the
resulting residue was dissolved in ether. This
ether solution was treated with an excess of maleic
acid, also in ether. The resulting precipitate
comprising the maleate salt of trans-dl-2-acetyl-
5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-
octahydropyrrolo[3,4-glquinoline melted at 179-
180C. after crystallization from a methanol-ether
solvent mixture; yield = 280 mg.
Analysis Calculated: C, 61.59; H, 7.19; N, 6.25;
Found: C, 61.32; H, 6.37; N, 6.53.
690 mg. of trans-dl-2-acetyl-5-n-propyl-
7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-
t3,4-g]quinoline maleate were dissolved in ethanol
and this solution added to a solution containing an
excess of sodium ethylate in ethanol. The reaction
S750
X-50~0s
-40-
mixture was stirred for 1~2 hour after which time it
was diluted with water and the aqueous mixture
extracted with chloroform. The chloroform extract
was separated, washed with saturated aqueous sodium
chloride and then dried. Evaporation of the chloro-
form yielded trans-dl-5-n-propyl-7-ethoxycaxbonyl-
4,4a,5,6,7,8,8a,9-octahydropyrrolo[3,4-g]quinoline
formed in the above reaction. The free base melted
at 163-4C. after recrystallization from ethanol.
Analysis calculated: C, 70.31; H, 9.02; N, 9.65
Found: C, 70.22; H, 8.91; N, 9.94.
About 1/2 gram of trans-dl-5-n-propyl-7-
ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-
[3,4-g]quinoline were dissolved in 75 ml. of tetra-
hydrofuran. 1 g. of lithium aluminumhydride was
added thereto in small portions. After all of the
lithium aluminumhydride had been added, the reaction
mixture was stirred for another 2.25 hours after
which time the excess lithium aluminumhydride was
decomposed by the addition of ethyl acetate and any
organometallic salts present decomposed by the
addition of 10% aqueous sodium hydroxide. The
resulting mixture was diluted with water and the
aqueous layer extracted several times with chloro-
form. The chloroform extracts were separated and
combined and the combined extracts washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded as a residue,
trans-dl-5-n-propyl-7-hydroxymethyl-4,4a,5,6,7,8,-
8a,9-octahydropyrrolo[3,4-g]quinoline, which melted
11~5750
X- 5 0 ~; O B
--41--
at 178-180C. after recrystallization from a ethyl
ace~ate/ether solvent mixture.
Analysis calculated: C, 72.54; H, 9.74; N, 11.28
Found: C, 72.30; H, 9.73; N, 11.05.
About 0.4 g. cf trans-dl-5-n-propyl-
7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-
[3,4-g]quinoline were dissolved in 25 ml. of pyridine.
0.5 ml. of methanesulfonyl chloride were added and
the resulting mixture stirred for 0.75 hours at room
temperature. The reaction mixture was dilu~ed with
water and sufficient 14N aqueous a nium hydroxide
added to make the reaction mix~ure basic. The
a~US mixture was extracted several times with
ethyl acetate. The ethyl acetate extracts were
combined and the combined extracts washed first with
water and then with saturated aqueous ammonium
chloride and were then dried. The residue obtained
by evaporation of the æolvent was chromatographed
over 30 g. of "Plorisil'~' and the chromatogram ~lq~
with chloroform containing increasing quantities
~2-4%) of methanol as the eluant. Fractions shown
by thin-layer chromatography to contain the desired
methanesulfonyl ester were combined and the solvent
re ved ~herefrom ln _acuo. The resulting residue,
tran-~-dl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,-
8,8a,9-octahydropyrrolo[3,4-g]quinoline was crys-
tallized from ethanol; m.p. = 150C. with decomposi-
tion.
57SO
X-5()60B
--42--
FINAL PRODUCTS
Example 1
Preparation of trans-dl-5-Methyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrrolo[3,4-g]ql~inoline from the
Corresponding 2-Acetyl Compound.
One and two-tenths grams of trans-dl-
2-acetyl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-
pyrrolo[3, 4-g] quinoline maleate were suspended in
100 ml. of methanol and 10 ml. of 2N aqueous sodium
hydroxide were added. The resulting mixture was
stirred at room temperature under a nitrogen
atmosphere for about 35 minutes and was then diluted
with dilute aqueous sodium hydroxide. The resulting
alkaline solution was extracted several ~imes with
chloroform. The chloroform extracts were combined
and the combined extracts washed with saturated
aqueous sodium chloride and dried. Evaporatisn of
the chloroform yielded 400 ml. of crystalline
material melting at 190-6C. with decomposition. A
chloroform solution of the material was then
chromatographed o~er 30 g. of "Floris~" using chloro-
form containing increasing amounts (2-5%~ of
methanol as the eluant. The second major component
to be eluted from the column consisted of trans-
dl-S-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-
13,4-g]quinoline. Fractions containing this
compound were combined and the solvent removed from
the combined fractions by evaporation. Recrystal-
lization of the residue from ether yielded trans-
i~s~so
,~-5060B
--43--
dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-
t3,4-g]quinoline melting at 200-222C. with decom-
position (80 mg.).
Analysis: calc.: C, 75.74 H, 9.53; N, 14.72;
Found : C, 75,8B H, 9.28; N, 14.55.
Following the above procedure, trans-
dl-2-acetyl-5-n-propyl-4,4a,5,6,7,8,8a,9-octa-
hydro-2H-pyrrolo[3,4-g}quinoline (4.8 g) was
hydrolyzed with dilute aqueous sodium hydroxide.
c trans-dl-5-n-Propyl-4,4a,5,6,7,8,8a,9-octahydro-
2H-pyrrolo[3,4-g]quinoline thus prepared was
purified by ch~omotography over UFlorisil''using
chloroform containing increasing amounts (2-10%)
methanol as the eluant. Fractions shown to contain
the desired product by TLC were combined and the
solvent evaporated therefrom. Recrystallization of
the residue from a methanol-ether solvent mixture
yielded 245 mg. crystalline trans-dl-5-n-propyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quino-
Zo line melting at 169-171C. with decomposition; nmr
peaks at 52, 384 and 510 cps. (in CDC13).
Analysis: calc.: C, 64.65; H, 7.84; N, 8.38;
~ound : C, 64.40; H, 7.62; N, 8.12.
Example 2
Preparation of trans-dl-5-n-Propyl-4,4a,5,6,7,8,-
8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
The product trans-dl-2-acetyl-5-n-propyl-
4,4a,5,6,7,8,Ba,9-octahydro-2H-pyrrolo[3,4-g]quinoline
(from Example B~ was dissolved in 20 ml. of methanol
3o
. . ' .
.
.
1145750
-5060B
-44-
to which was added 3 ml. of ZN aqueous sodium
hydroxide. This reaction mixture was stirred at
ambient temperature under a nitrogen atmosphere for
65 min. The reaction mixture was diluted with water
and the diluted mixture extracted several times with
chloroform. The chloroform extracts were combined
and the combined extracts washed with saturated
aqueous sodium chloride and then dried. Evaporation
of the chloroform yielded a residue which was shown
to contain one major spot by TLC. An ether solution
of the xesidue, comprising trans-dl-5-n-propyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quino-
line formed in the above reaction, was treated with
an excess of maleic acid in ether solution, thus
forming the maleate salt of the base. The maleate
salt was separated by filtration and recrystallized
from an ether-methanol solvent mixture. trans-dl-
5-n-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-
~3,4-g]quinoline maleate thus prepared melted
168-170C, with decomposition; yield - 215 mg.
Example 3
The mesylate ester (prepared in Example F)
can be reacted with the sodium salt of methyl-
mercaptan to yield trans-dl-5-n-propyl-7-methyl-
mercaptomethyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-
13,4-g]quinoline.
As evidence of the utility of the compounds
of formula I, it has been found that they affect
turning behavior in rats in a test procedure
,
. ~ - - ~ .
57SO
X-5060B
--45--
designed to uncover compounds useful for the
treatment of Parkinsonism utilizing 6-hydroxy-
dopamine-lesioned rats. In this test, nigro-
neostriatal-lesioned rats are employed, as prepared
by the procedure of Ung~erstedt and Arbuthnott, ~rain
Res, 24, 485 ~1970). A compound having dopamine
agonist activity causes the rats to turn in circles
contralateral to the side of the lesion. After a
latency period, which varies from compound to
compound, the number of turns is ~ounted over a
15-minute period.
Results obtained from testing representa-
tive compounds of formula I in the rat turning test
are set forth in Table 1 below. The compounds were
dissolved in water and the aqueous solution injected
into the rat by the intraperitoneal route at a dose
level of 1 mg/kg. In the table, column 1 gives the
name of the compound, column 2, percent of test
animals exhibiting turning behavior, and column 3,
avexage number of turns observed in first 15 minutes
after end of latency period.
57SO
X--5060B
--46--
q) O
a
~1
0 ~ C h
0
o
D;-r~-r~ ~ O
~ ~ ~ _~
O ~ ~
~ E~ m
~P ~
~1
_~ ~ Q) 1--
.a
E~ U~ O
O
~a I ~ ~1 ` ~
~ _~ I O c Q,
O 1~ rl
C~ O ~ ~
~ . ~ o ~
U C ~ I
I 0~ I ~1
O U~ o
I, ~ I (a a~
'O ~ U-~
~ I 1~ _1 1 0--~
Z ~ C~ C I ~
h
,
,
-5060B 114S750
--47--
The compounds of formula I are also
useful as prolactin inhibitors and as such they can
be employed in the treatment of inappropriate
lactation such as postpartum lactation and galac-
torrhea. As evidence of their utility in thetreatment of diseases such as those in which it is
desirable to reduce the prolactin level, the com-
pounds of formula I have been shown to inhibit
prolactin according to the following procedure.
Adult male rats of the Spraque-Dawley
strain weighing about 200 g. were housed in an
air-conditioned room with controlled lighting
(lights on 6 a.m. - 8 p.m.)-and fed lab chow and
water ad libitum. Each rat received an intra-
peritoneal injection of 2.0 mg. of reserpine in
aqueous ~uspension 18 hours before administration of
the test drug. The purpose of the reserpine was to
keep prolactin levels uniformly elevated. The
compounds under test were disQolved in 10 percent
ethanol, and were injected intraperitoneally at
doses of 0.5 and 5 mg/kg. Each compound was ad-
ministered at each dose level to a group of 10 rats,
and a control group of 10 intact males received an
equivalent amount of 10 percent ethanol. One hour
after treatment, all rats were killed by decapita-
tion, and 150 ~1 aliquots of serum were assayed for
prolactin.
The difference between the prolactin level
of the treated rats and prolactin level of the
control rat~, divided by the prolactin level of the
5750
X-5060B
--48--
control rats gives the percent inhibition of
prolactin secretion attributable to the compounds of
formula I. These inhibition percentages are given
in Table 2 below. In the table, column 1 gives the
name of the compound; and columns 2 and 3 ! the
percent prolactin inhibition at the 0.5 and 5 mg/kg
dose levels.
,..
1~5750
X-5060B
--49--
.
o
~:
S ~ ~
a ~ Ll o
~ ~ a~ cn
O U~
.,~
C)
~ .Y
O ~ I
I
~ D.
a~ ~ In
_~ C Q
~ U
E~
P.
0,
O O
' ~ `
l O ~ `~ _
o
:~ O S Q~
O ~ ~ C ~: ~1 C
l~ J- rl ~ S-rl
O C O O ~:~ O
C.~ I I C I
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q~
O
~ 00
a~ I ' ~ I ~
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:Z
. i~45750
A-5060B
--50--
In using the compounds of formula I
to inhibit prolactin secretion or to treat Parkinson's
syndrome or for other pharmacologic action, a com-
pound according to formula I above in which R2 is
S Cl-C3 alkyl or allyl and Rl is H or Cl-C3 alkyl, or a
salt thereof with a pharmaceutically-acceptable acid,
is administered to a subject suffering from Parkin-
sonism or in need of having his prolactin level
reduced in an effective amount to treat Parkinsonism
or to reduce prolactin. Oral administration is
preferred. If parenteral administration is used, the
injection is preferably by the subcutaneous route
using an appropriate pharmaceutical formulation.
Other modes of parenteral administration such as
intraperitoneal, intramuscular, or intra~enous routes
are equally effective. In particular, wi~h intra-
venous or intramuscular administration, a water
soluble pharmaceutically-acceptable salt is employed.
For oral administration, the compound either as the
free base or in the form of a ~alt thereof can also
be mixed w$th standard pharmaceutical excipients and
loaded into empty telescoping gelatin capsules or
pressed into tablets. For oral administration, the
compound either as the free base or in the form of a
salt thereof, can also be mix~d with standard
pharmaceutical excipients and loaded into empty
telescoping gelatin capsules or pressed into tablets.
~he oral dosage range is from about 0.01 to 10 mg. to
10 mg./kg. of mammalian weight and the parenteral
dose range from about 0.0025 to 2.5 mg./kg. Intra-
` 114S7SO
X-5060B
peritoneal dosages of 10-30 mg./kg. of trans-
dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-pyrrolo-
13,4-g]-quinoline dihydrochloride resulted in no
- deaths, but dosages of 100-300 mg./kg. were fatal,
indicating an LD50 in the range 30-100 mg./kg.
