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Патент USA US3079399

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3,079,395
Patented Feb. 26, 1963
2
(c) subjecting Compound III to hydrolysis-decarboxyla
tion, thereby forming a compound having the formula
3,079,395
N()VEL Z-OX?-BENZOQUlNGLIZINE
DERIVATIVES
Arnold Brossi and Otto Schnider, Basel, Switzerland, as
signors to Ho?‘mann-La Roche, Inc., Nutiey, N.J., a
corporation of New Jersey
No Drawing. Filed Mar. ‘26, 1958, Ser. No. 723,977
Claims priority, application Switzerland Apr. 2, 1957
11 Claims. (Cl. 260—287)
(IV)
X/
I!
This invention relates to Z-oxo-benzoquinolizine deriva
0
tives, and to novel processes and novel intermediates use
wherein X has the same meaning indicated above.
ful in the preparation thereof.
In one comprehensive embodiment, the invention pro
The l-lower carbalkoxymethyl-l,2,3,4-tetrahydroisoquin
olines of Formula I above, required as starting ma
terials, can be produced according to methods known per
vides a process which comprises (a) reacting a com
pound having the formula
(1)
se [cf. J. Chem. Soc. (London), 1951, 3472, and 1953,
q
2465] by reaction of the corresponding ?-substituted
ethylamines with malonic acid ester, cyclization of the
\
NH
thus obtained half ester-amides, and catalytic hydrogena
20 tion of the cyclized products.
‘In the ?rst stage (a) of the comprehensive embodiment
CHr-C O O-lower alkyl
referred to above, the lower carbalkoxymethyl~tetrahy
droisoquinoline starting material, Formula I above, is
wherein X represents a divalent radical selected from
condensed with a lower alkyl acrylate (e.g. methyl acryl
the group consisting of buta-l,3-dien-l,4-ylene, i.e.
X/k
ate, ethyl acrylate, etc.) or with a lower alkyl B-halo
—CH=CH—CH=CH-
propionate (e.g. methyl ,B-chloropropionate, ethyl IS-bro
mono(lower alkoxy)-buta-l,3-dien-l,4-ylene, e.g.
mopropionate, etc.). The condensation is effected, for
example, at a temperature between about 50° C. and
about 100° C. In the event that an acrylic acid ester
——-CH=C—OH=GH—
H300
is selected as one of the reactants, added solvent is super
fluous. It is nevertheless advantageous to use an excess
di(lower alkoxy)-buta-l,3-dien-l,4-ylene, e.g.
--CH=C—O=GH~—
of the acrylic acid ester, for example, ten times the theo
H300 OCHt
retically required quantity. On the other hand, if the
tri(lower alkoxy)-buta-1,3-dien-l,4-ylene, e. g.
35 condensation is effected by means ‘of a ?-halopropionic
acid ester, the reaction is advantageously carried out in
an organic solvent, e.g. acetone or benzene, and in the
presence of an acid binding agent, e.g. potassium carbon
l
I
mot!) OOH; 00m
and lower alkylenedioxy-buta-1,3-clien-1,4-ylene, cg.
40
ate. The ?-[l-lower carba1koxymethyl-tetrahydroiso~
quinolinyl-(Z)J-propio-nic acid esters of Formula II, ob~
taiued as products of the ?rst stage (a) referred to above,
with a member selected from the group consisting of
lower alkyl acrylate, e.g. CHFCH~—COOCH3 or
are compounds of basic character; they are soluble in
acids, but are insoluble in water and alkalis.
In the second stage (12) of the comprehensive embodi—
ment referred to above, the di-esters of Formula II are
converted by ring closure via a Dieckmann reaction to
CH3=CH—COO—n-C3H7
hexahydro - llbi-I - benzo[a]quinolizines, Formula III
-—CH=C
0:011
0-OHz-O
and lower alkyl ti-halopropionate, e.g.
BrCH2CH2CGOCH3 or ClCH2CI-I2COOC2H5
thereby forming a compound having the formula
(11)
X
G
above——numh-ering per “Ring Index” No. 1957. It is
appropriate to effect the cyclization in an inert solvent,
e.g. benzene, ether or toluene, in the presence of a con
ventional condensation agent, e.g. an alkali metal alco
holate, boron tri?uoride or sodium hydride. In a pre—
ferred mode of execution, the di-ester, in dry benzene
:k/N—GH:—CH2 O O 0 -lower alkyl
1
CH2-C O 0 -lower alkyl
wherein X has the same meaning indicated above; (b)
cyclizing Compound II, thereby forming a compound
having the formula
(III)
the corresponding 2-oxo-3-lower carbalkoxy-l,2,3,4,6,7
and in the presence of sodium ethylate, is heated while
continuously removing by azeotropic distillation the alco- ,
hol formed by condensation. The quinolizine derivatives
of Formula III above, thus obtained, are basic com
pounds, which are easily soluble in acids and in the ordi
0 nary organic solvents, e.g. ethanol. They exhibit the
typical enol reaction with ferric chloride. They are use
ful as intermediates for the preparation of a variety of
substituted benzoquinolizines, as indicated below.
1In the third stage (0) of the comprehensive embodi~
.
ll 7“
65 ment referred to above, the esters of Formula III are
subjected to hydrolysis-dccarboxylation. This step can
2
——G O O-lower alkyl
l
0
wherein X has the same meaning indicated above; and
be effected according to methods known per se. The
splitting off of the carbalkoxy group can be effected both
by treatment with acidic reagents, for example mineral
70 acids, such as aqueous hydrochloric acid; and alkaline
reagents, for example alkaline lyes, such as dilute aqueous
sodium hydroxide solution. According to a preferred
mode of execution, the compounds of Formula III above
8,079,395
4
3
saturated-hydrocarbyl compounds of Formula ‘VII by con
are re?uxed with 3 N aqueous hydrochloric acid solution.
In a second comprehensive embodiment, the invention
ventional methods.
The last stage (c) in the second comprehensive embodi
ment referred to above comprises such reduction. Reduc
tion can be effected, for example, by reaction with cata
provides a process which comprises (a) reacting a com
pound of Formula III above with a non-benzenoid 1
halohy'clrocarbon which is unsaturated in ?-position to
the halogen atom, thereby forming a compound having the
formula
(V)
x/\m
l
lytically activated hydrogen. Appropriate catalysts are
Raney nickel oripalladium-on-carbonir It is advantageous
to-etfect the catalytic reduction in an inert organic solvent,
e.g. methanol or ethanol.
10
\ N
In a third comprehensive embodiment, the invention
provides a process which'comprises '(a) reducing a com
pound'of Formula V above-,thereby forming a compound
having the formula
‘ R
(VIII)
C O O-lower alkyl
15
0
wherein _X represents‘a divalent radical selected fromv the
group consisting of buta~l,3r-dien-l,4~_ylene; mono(lower
alkoxy)-buta-l_,3¥dien-‘l,4éylene; _|di('lower alkoxy)-buta
LB-dien-ILAe-ylene; tri(lower alkoxy)-btita-l_,3-dien-l_,4
ylene, and lower alkylenedioxy-buta-l,3~dien-l,4~ylene;
20
l1
and'eR represents a monovalent non7benzenoid ?-unsatm
wherein each of X and Z has the samelmeaning indicated
rated hydrocarbon radical; (if) subjecting Compound V
to hydrolysis-decarboxylation, thereby forming a com
pound having‘ the formula
C O O-loweralkyl
0
above; and (b) subjecting Compound‘ VIII to hydrolysis—
25 decarboxylation, thereby forming a compound having
Formula VII above.
(VI)
The ?rst stage (a) of this third comprehensive embodi
ment comprises reduction of the 2-oxo-3-lower carbalk
oxy-S?-unsaturatedhydrocarbyl benzoquinolizine com
30 pound of Formula V to the corresponding 2-oxo-3-lower
carbalkoxy-3-B-saturated-hydrocarbyl compound of For
35
wherein each of X and R has the same meaningtindicat'ed
above; and (c) hydrogenating Compound VI,‘ thereby
forming a compound having the formula‘
one
i
mula VIII. This reduction can ‘be eifected by methods
'known per se, e.g. by catalytic reduction. The reduc
tion is advantageously effected in a solvent such-as a lower
alkanol. ~Raney nickel and palladium-on-carbon hydro
genation catalysts are suitable‘ for this stage.
The second stage (b) of the third comprehensive em
bodiment referred to above comprises hydrolysis and de
carboxylation- of the-intermediate of Formula VIII‘ to the
40
2-0xo-3-{3 - saturated-hydrocarbyl - hexahydrobenzoquim
olizine of Formula VII. The hydrolysis’ and decarboxyla
tion can be effected ‘both'by reaction with acidic and with
alkaline )hydrolyzing agents. In a preferred mode of
execution, the hydrolysis is etfected by means of dilute
45 mineral acid, e.g. 3 N aqueous hydrochloric acid.
H
The 2-oxo-hexahydro-1lbH-benzo[a]quiuolizines of
0
Formula IV above and the 2-oxo-3-hydrocarbyl-hexahy
dro-l1bH-benzo[a] quinolizines of Formulas VI and VII
wherein X has the same meaning indicated above and Z
above are'base's which are only dif?cultly soluble in‘ water.
represents a mouovalent non-ben'zenoid ?~saturated hydro
50 However, they form acid addition salts which are readily
soluble in water, with the acids ordinarily employed for
Illustrative non-benzenoid l-halohydrocarbons unsatu
the preparation of pharmaceuticals; e.g., inorganic acids,
rated in theft-position which can be’ employed in the ?rst
such as hydrochloric and phosphoric acids; organic acids,
step (a) of the second comprehensive embodiment re
such as tartaric, acetic and citric acids; and the like. The
‘ferred to above are, for example,’ allyl bromide, methallyl
‘bases and their salts have pharmacological activity, for
chloride, q},'y-dimethylallyl bromide, propargyl bromide
example as narcosis—potentiat0rs; and are useful as medic
and Z-cyclohexen-l-yl bromide. The reaction of compound
inal agents, more particularly as reserpine-like tranquilliz'
III with the non-benzenoid l-halohydrocarbon can be ef
fe'cted in an aqueous. lye in the presence of a' catalytic
ing agents.
carbon
radical.
,
I
e I
The invention is further disclosed in the following ex
quantity of copper. In a preferred mode of execution of
this stage, the keto-ester, Compound III, is stirred with the 60 amples, which are illustrative but not limitative thereof.
Temperatures are stated in degrees centigrade.
non-bienzeno'id l-halohydrocarbon in. the presence of a
little copper powder and in the calculated quantity of an
Example 1
aqueous lye. .
_
The second stage ‘(-11)’ of the second comprehensive em
bodiment referred to above comprises hydrolysis and de
carboxylation to the corresponding 2-oxo-3-unsaturated
54 g. of 1 - carbethoxyrnethyl-6,7-dimethoxy-1,2,3,4
65 tetrahydroisoquinoline and 100 cc. of ethyl acrylate were
hydro'carbyl compound. If the radical R which is present
in the 3-p‘osition of Compound V is an alkenyl radical,
it'is advantageous to effect the hydrolysis-decarboxyla
tion by heating Compound V in alkaline medium. Ac 70
cording to a preferred’ mode of execution, the 3-alker1yl~3
lower carbalkoxy-Z-oxo compound of Formula V is re
?uxed in alcoholic sodium hydroxide solution. The 3-13
unsaturated-hydrocar-byl-substituted compounds of For
re?uxed for 24 hours. The reaction’ mixture was cooled,
and diluted with an equal volume of ether, and the basic
portions were extracted with 3 N hydrochloric acid.
The hydrochloric acid extract was mixed with ammonia
solution, while cooling with ice, until the mixture reacted
alkaline to phenolphthalein, and the bases which sep->
arated were taken up in ether. The ethereal solution was
dried over sodium sulfate, ?ltered and concentrated, and
the residue was distilled in high vacuum. There was thus
mula VI can be reduced to the corresponding 2-oxo-3-p 75 obtained 65 g. of ?~£l-carbethoxymethyl-6J-dimethoxy-
3,079,395
6
1,2,3,4-tetrahydroisoquinolyl-(2)]-propionic acid ethyl
Example 4
ester, which distilled between 197°~201° at 0.02 mm.,
nD22=1.5235. After standing for some time, the distillate
solidi?ed, MP. 37°-39° after recrystallization from low
12 g. of 1-carbethoxymethyl-6-methoxy-1,2,3,4-tetrahy
droisoquinoline was condensed with ethyl acrylate, sim
ilarly to Example 1. The ,8-[l-carbethoxymethy1-6
boiling petroleum ether.
methoxy-1,2,3,4-tetrahydroisoquinolyl - (2)] - propionic
2.49 g. of sodium was dissolved in 90 cc. of absolute
ethyl alcohol and the solvent was distilled off in a water
pump vacuum. To the dry sodium ethylate was then
acid ethyl ester produced was puri?ed by distillation in
high vacuum, yielding 12 g. of a colorless oil, B.P. 170°
175 °/0.03 mm., nD24=1.5l68. The Dieckmann conden
sation reaction, effected according to the indications in
added 34.2 g. of ,8-[l-carbethoxymethyl-6,7-dimethoxy~
1,2,3,4-tetrahydroisoquinolyl-(2)J-prop-ionic acid ethyl
ester dissolved in 600 cc. of dry ‘benzene. The reaction
mixture was heated while stirring, and alcohol formed
by condensation was distilled o? azeotropically. The dis
10 Example 1, yielded 5.3 g. of 2-oxo-3-carbethoxy-9
methoxy - 1,2,3,4,6,7 - hexahydro-llbH-benzo[a]quinol—
izine of M.P. 132°.
The keto ester gave a violet enol
reaction with ferric chloride.
4.7 g. of the keto ester in 50 cc. of 20% hydrochloric
tillation was interrupted when the temperature reached
8°.
Then the reaction mixture was re?uxed for one 15
acid was re?uxed for % hour After concentration of the
residue there was obtained 3.5 g. of 2-oxo-9-methoxy
solution and water until the ‘benzene solution no longer
1,2,3,4,6,7 - hexahydro-11bl-l-benzo[a] quinolizine hydro
gave an enol reaction with ferric chloride. The aqueous
chloride, M.P. 198°—199° after recrystallization from
alkaline extracts were combined, cooled with ice and then
carbon dioxide was introduced. In this manner there was 20 80% acetic acid-ether.
hour, cooled and extracted with 3 N sodium hydroxide
The starting material, 1-carbethoxymethyl-6-methoxy
obtained 18 g. of 2-oxo-3-carbethoxy-9,IO-dimethoxy
1,2,3,4-tetrahydroisoquinoline, was obtained from m-meth
1,2,3,4,6,7 - hexahydro-llbH-benzo[a] quinolizine, which
melted at l14°—ll5° after recrystallization from alcohol.
The hydrochloride, prepared by means of alcoholic
oxyphenylethylamine (J. Chem. Soc. London, 1956, 329)
as follows: Condensation with diethyl malonate yielded m
methoxyphenylethylnnalonic acid half ester amide, which
crystallized from petroleum ether in the form of ?ne
needles having MP. 42°. Cyclization of the half ester
amide with phosphorus oxychloride in benzene and cata
lytic hydrogenation of the thus obtained dihydro base in
glacial acetic acid with platinum dioxide yielded the de
ethereal hydrogen chloride, melted at 193 °—l94°, after
recrystallization from alcohol-ether.
11 g. of the keto carboxyiic acid ester was dissolved in
100 cc. of 3 N hydrochloric acid and re?uxed for 5 hours.
The reaction mixture was cooled, washed with ether, and
made alkaline to phenolphthalein ‘by addition of ammonia. 30
sired tetrahydroisoquinoline. The oxalate, prepared by
After standing in the cold, 8.0 g. of 2-oxo-9,10~dimethoxy
1,2,3,4,6,7-hexahydro-l lbH-benzo [a] quinolizine crystal
means of oxalic acid in acetone, melted at 148°-l50°.
lized, M.P. 150°—151° after recrystallization from metha
nol. The hydrochloride, prepared by means of alcoholic
ethereal HCl, melted at 160°—l61°. A form containing
mm., nD24=1.5357.
The base, liberated from the oxalate by potassium carbo
nate solution, is a light yellow oil of B.P. 130°—132°/0.02
Example 5
12 g. of 1-carbethoxymethyl-6,7-methylenedioxy-1,2,3,
one mol of water of crystallization also crystallized, M.P.
151°—152°.
4~tetrahydroisoquinoline and 24 cc. of ethyl acrylate were
condensed according to the indications in Example 1.
Example 2
9.0 g. of 1-carbethoxymethyl-6,7-dimethoxy-1,2,31,4 40 The di-ester obtained was distilled in high vacuum, B.P.
180°-183°/0.01mm. (11g).
tetrahydroisoquinoline was dissolved in 30 cc. of acetone,
11 g. of the di-ester was cyclized by a Dieckmann re
15 g. of dry potassium carbonate and 6 g. of ethyl {3
action according to Example 1, yielding 4.3 g. of 2-oxo
-bromopropionate were added, and the mixture was re
3-carbethoxy-9,ltl-methyleuedioxy - 1,2,3,4,6,7 - hexahy
?uxed for 24- hours while stirring. The reaction mixture
dro~11bH-benzo[a]quinolizine having M.P. 126°. Enol
was ?ltered and the residue was washed with acetone; the
reaction with ferric chloride.
washings were added to the ?ltrate, and the combined
liquors were concentrated. The residue was dissolved in
ether and the ‘basic portions were extracted with 3 N
HCl. The HCl extract was made alkaline to phenol
phthalein by addition of ammonia and was then extracted
with ether.
' 3 of the keto ester, upon hydrolysis and decarboxyla
tion with 3 N HCl according to the indications in Ex
ample 1, yielded 2 g. of 2-oxo-9,10-methylenediox‘ -1,2,3,
4,6,7-hexahydro-1 lbllbenzo [a] quinolizine hydrochloride
of MP. 200°. The base, liberated from the hydrochlo
ride by sodium hydroxide solution, melted at 14l°—l42°
after recrystallization from alcohol.
The extract was dried over sodium sulfate,
?ltered, concentrated and the residue was distilled in high
vacuum.
There was thus obtained 6.5 g. of ?-[l-car
The starting material required, 1-carbethoXymethyl-6,7—
methylenedioxy-l,2,3,4-tetrahydroisoquinoline, was ob
lbethoxymethyl - 6,7 - dimethoxy - 1,2,3,4 - tetrahydroiso
quinolyl-(2) ]-propionic acid ethyl ester, which distilled at
The distillate solidi?ed upon
tained from homopiperonylamine as follows: Condensa
cooling; a sample, recrystallized from petroleum ether,
tion with diethyl malonate yielded the half ester amide,
190—200° at 0.02 mm.
M.P. 96-98".
was identical with the preparation of Example 1, accord
tions.
Cyclization, saponi?cation and decarboxylation, effected
00
methyl-6,7-methylenedioxy-3,4~dihydroisoquinoline, yel
low crystals, M.P. 144—146°. Catalytic hydrogenation of
the latter in glacial acetic acid with platinum oxide cata
according to the indications in Example 1, yielded 2-oxo
lyst yielded the required tetrahydroisoquinoline, B.P.
9,10 - dimethoxy - l,2,3,4,6,7-hexahydro-l1bH-benzo[a]
145°/0.03 mm, M.P. 58°.
quinolizine, MP. 150°-—15l°.
Example 3
Cyclization of the half ester amide with
phosphorus oxychloride in benzene yielded l-carbethoxy
ing to melting point and mixed melting point determina
(i5
Example 6
12 g. of 1-carbethoxymethyl-6,7,8-trimethoxy-1,2,3,4
tetrahydroisoquinoline and 24 cc. of ethyl acrylate were
condensed according to the indications in Example 1.
The
di-ester, obtained by working up in the manner
pared according to Example 1, was dissolved in 100 cc.
70 previously indicated, was distilled in high vacuum, B.P.
of absolute benzene, mixed with 2.9 g. of sodium hydride
36.5 g. of B-[l-carbethoxymethyl-6,7-dimethoxy-1,2,3,4
tetrahydroisoquinolyl-(2) ]-propionic acid ethyl ester, pre
and refluxed for one hour.
The reaction mixture was
worked up in the manner indicated in Example 1, yielding
15 g. of 2-oxo-3-carbethoxy-9,IO-dimethoxy-1,2,3,4,6,7
hexahydrodlbH-benzo[a] quinolizine, MP. 1l4°-115°.
180°/0.01 mm. 12 g. of the di-ester, upon Dieckmann
condensation according to Example 1, yielded 4.6 g. of
the corresponding keto ester having M.P. 106°; violet
enol reaction with ferric chloride. Hydrolysis and de
carboxylation, as in the previous examples, yielded 3.5 g.
3,079,395
of 2-oxo-9,10,1l-trimethoxy-1,2,3;4,6,7-hexahydro-1lbl-I
benzo[a]quinolizine hydrochloride, M.P. 190°. Base,
M.P. 105 °.
The required starting material, 1-carbethoXymethyl-6,7,
B-trimethoxy-1,2,3,4-tetrahydroisoquinoline, was obtained
from mescaline as follows: Condensation with diethyl
malonate to the half ester amide, M.P. 67°; cyclization
with phosphorus oxychloride in benzene to l-carbethoxy
methyl - 6,7,8 - trimethoxy-3,4-dihydroisoquinoline, M.P.
8
hydro-1lbH-benao[a]quinolizine, obtained according to
Example 7, was dissolved in 300 cc. of methanol and by
drogenated at room temperature with 2 g; of Raney
nickel. After the theoretical amount of hydrogen had
been taken up, the hydrogenation was interrupted, the
catalyst was ?ltered o? and the ?ltrate was concentrated.
There was thus obtained 8.0 g. of 2-oxo-3-n-propyl-9,10
dimethoxy - 1,2,3,4,6,7 - hexahydro-l1bH-benzo[a]quino
lizine, M.P. 102° after crystallization from alcohol-water.
120°; and catalytic hydrogenation in glacial acetic acid 10 This preparation was identical with that prepared in Ex
with platinum oxide catalyst to the desired product, a light
yellow liquid having BI’. 168°/0.01 mm.
ample 8. >
In similar manner, catalytic hydrogenationv of the ke
tones prepared in Example 7, in ethanol using palladium
carbon catalyst, resulted in the following quinolizines:
Example 7
19.8 g. of 2-oxo-3lcarbethoxy-9,10-dimethoxy-1,2,3,4,6, 15
7 -hexahydro-1 1bH-benzo[a] quinolizine, prepared accord
ing to Example 1, was mixed with 60 cc. of water and 5.6 '
2 - oxo - 3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahy
dro-l lbH~benzo[a]quinolizine, M.P. 123°.
mide, M.P. 202°.
Hydrobro
2 - oxo - 3-isoamy1-9,IO-dimethoxy-1,2,3,4,6,7-hexahy
cc. of freshly distilled allyl'bromide. 200 mg. of copper
dro-1'1bH-benzo[a]quinolizine, M.P. 106°. Hydrobro
powder was added and the mixture was stirred vigorously
While adding dropwise 61 cc. of 1 N sodium hydroxide 20 mide, M.P. 196°.
solution; After the addition was completed, the mixture
We claim:
11‘. A process which comprises reacting at a tempera
The
ture between about 50° C. and about 100° C. a com—
oil‘which separated was taken up in ether, the ether solu
tion was washed with a_3 N NaOl-i solution and then with
pound‘having the formula
water, and then was extracted with 3 N hydrochloric acid 25
‘was‘stirred for an additionalperiod of ' 30 minutes;
solution. Upon standing overnight, 10.8 g; of the hydro
chloride of 2-oxo-3-allyl-3lcarbethoxy-9,10idimethoxy-1,
2,3,4,6,7-hexahydro - llbH - benzo [a] quinolizine crystal
NH
lized, M.P. 156°. The keto-ester base, liberated from the
hydrochloride by alkali, crystallized from alcohol in the
CHz-C O O-lower alkyl
form of prisms having M.P. 118°. The keto-ester base
wherein X represents a divalent radical selected from the
gave no color reaction upon mixing with alcoholic ferric
group consisting of buta-1,3-dien-1,4-ylene; mono(lower
chloride solution.
alkoxy)buta-1,3-dien-l,4-ylene; di(lower a1koxy)~buta-1,
10 g. of 2-oxo-3-allyl-3-carbethoxy-9,10-dimethoxy-1,2,
3-dien-l,4-ylene; _tri-(1ower alkoxy)-buta-1,3-dien-1,4-yl<
3,4,6,7-hexahydro-1lbH-benzo[a]quinolizine was re?uxed 35 ene; and lower alkylenedioxybuta-1,3-dien-'1,4-ylene; with
for three hours in 300 cc. of 5% alcoholic sodium hy
a member selected from the group consisting of lower‘
droxide solution; The reaction mixture was concentrated
alkyl acrylate and lower alkyl ?-halopropionate, thereby
in vacuo,.mixed»with water, ?ltered, dried, and the resi-v
forming a compound having the formula
due was recrystallized from ethyl acetate-petroleum. ether.
There was thus obtained 3.5 g. of 2-oxo-3-allyl-9,10-di 40
methoxy-l ,2,3,4,6,7-hexahydro-1 lbH-benzo [a] quinolizine
having. M.P. 114°—116°. Hydrobromide, M.P. 205°.
Oxime, M.P. 164°.
By working in the manner described in this example,
there were also prepared, from 2-oxo-3-carbethoxy-9,10
(BHrC O O-lower alkyl
wherein X has the same meaning indicated above; cycliz
dirnethoxy ~ 1,2,3,4,6,7 - hexahydro-1lbI-I'-benzo[a] quinol 45
ing the latter compound by heating it in an inert solvent
izine, by alkenylation with methallyl chloride and 7,7
in the presence of a condensing agent selected from the
dimethylallyl bromide, respectively, hydrolysis and decar
group consisting of an alkali metal alcoholate, boron tri
boxylation with alcoholic sodium hydroxide, the following
?uoride and alkali metal hydride, .thereby forming a
quinolizine-ketones :
compound having the formula
2-oxo-3-methallyl-9,IO-dimethoxy _ 1,2,3,4,6,7 - hexa 50
hydro-llbH-benzo[a]quinolizine, M.P. 138°;
Z-oxo-3-'y,'y-dimethylallyl—9,l?-dimethoxy - 1,2,3,4,6,7
hexahydro-l 1bH-benzo[a]quinolizine, M.P. 131°; hydro
bromide, M.P. 190°.
Example 8
55
9.4 g. of 2-oxo-3-allyl-3-carbethoxy-9,10-dirnethoxy-1,2,
3,4,6,7-hexahydro-11bH-benzo[a]quinolizine hydrochlo
ride, obtained according to Example 7, was dissolved in
.41,
til
O O O-lower nlkyl
0
300 cc. of ethanol and was hydrogenated with 3 g. of 5%
palladium-carbon catalyst. After the theoretical amount 60 wherein X has the same meaning indicated above; and
subjecting the latter compound to hydrolysis-decarboxyl
of hydrogen had been taken up, the reaction mixture was
?ltered, concentrated to dryness, dissolved in 300 cc. of
3 N HCl and re?uxed for six hours. The mixture was
washed with ether, made alkaline‘with sodium hydroxide
ation by treating it with a hydrolysis reagent selected
from the group consisting of mineral acids and alkaline
lyes, thereby forming a compound having the formula
solution, and the basic portions were extracted with ether. 65
The‘ residue was dissolved in acetone and mixed with alco
holic hydrogen chloride, whereupon 4.5 g. of 2-oxo-3-n
propyl - 9,10 - dirnethoxy-l,2,3,4,6,7-hexahydro-1lbH-ben- '
zo[a]quinolizine hydrochloride crystallized, M.P. 200°
202°. The base, liberated from the hydrochloride by the 70
action of alkali, melted at 102° after recrystallization
from methanol-water. Oxime, M.P. 158°.
‘
Example 9
10 g. of 2-oxo43-allyl-9g1O-dimethoxy-l,2,3,4,6,7-hexa 75 wherein X has the same meaning indicated above.
3,079,395
10%
2. A compound having the formula
palladium, thereby forming a compound having the for
mula
Ol
N
C 0 O-lower alkyl
10
wherein X represents a divalent radical selected from the
group consisting of buta~1,3-dien-1,4-ylene; mono(lower
alkoxy) -buta-1,3-dien-l,4-ylene; di(lower alkoxy) -buta-l,
3-dien-l,4-ylene; tri(lower alkoxy)-buta-1,3-dien-1,4-yl
wherein X has the same meaning indicated above and 2
represents a member of the group consisting of lower
15
one; and lower alkylenedioxy-buta-l,3-dien-l,4-y1ene.
3. A process which comprises reacting a compound
having the formula
4. A process which comprises reacting a compound
having the formula
20
W1
L/ 00 O-lower allryl
alkyl and cyclohexyl.
Xtl
O O O-lower alkyl
25
ll
0
wherein X represents a divalent radical selected from the
wherein X represents a divalent radical selected from the
group consisting of buta-1,3-dien-l,4-ylene; mono(lower
group consisting of buta-1,3-dien-1,4-ylene; mono?ower
alkoxy)-buta-1,3-dien-l,4-ylene; di(lower alkoxy)-buta
1,3-dien~l,4-ylene; tri(lower alkoxy)-buta-1,3-dien-l,4-yl
alkoxy)~buta-l,3-dien-l,4-ylene; di(lower alkoXy)-buta-l,
3-dien-l,4-ylene; tri(lower alkoxy)-buta-1,3-dien-1,4-yl
cue; and lower alkylenedioXy-buta-l,3-dien-l,4-yleue;
with a member of the group consisting B-unsaturated l~
halo-lower alkenyl, ,B-unsaturated l-halo-lower alkynyl,
one; and lower alkylenedioxybuta-1,3-dien-1,4-ylene; with
a member of the group consisting ?-unsaturated l-halo
35 lower alkenyl, B-unsaturated l-halo-lower alkynyl, and
[S-unsaturated 1~halocyc1ohexenyl, in an aqueous lye and
and B-unsaturated l-halocyclohexenyl, in an aqueous lye
and in the presence of a catalytic quantity of copper,
in the presence of a catalytic quantity of copper, thereby
forming a compound having the formula
thereby forming a compound having the formula
40
R
45
I \C 0 O-lower elkyl
I
\
C O O-Iower alkyl
0
0
wherein X represents a divalent radical selected from
wherein X represents a divalent radical selected from the
group consisting of buta-1,3-dien-1,4-ylene; mono(lower
50
alkoxy)-buta-l,3,dien-l,4-ylene; di(lower alkoxy)-buta
l,3-dien-'1,4-ylene; tri(lower alkoxy)buta-l,3-dien~1,4-yl
buta-1,3-dien-1,4-ylene; tri(lower alkoxy)-buta-1,3-dien-1,
4-ylene; and lower alkylenedioxybuta-1,3-dien-1,4-ylene;
ene; and lower alkylenedioxybuta-1,3-dien-1,4-ylene; and
and R represents a member of the group consisting of
R represents a member of the group consisting of B-un
saturated lower alkenyl, ?-unsaturated lower alkynyl, and
?-unsaturated cyclohexenyl; subjecting the latter com
pound to hydrolysis-decarboxylation by treating it with
a hydrolysis reagent selected from the group consisting
of mineral acids and alkaline lyes, thereby forming a
60
compound having the formula
N
L
the group consisting of buta-1,3-dien-1,4-ylene; mono(low
er alkoxy)-buta-1,3-dien-1,4-ylene; di(lower alkoxy)
B-unsaturated lower alkenyl, [B-unsaturated lower alkynyl,
and ?-uusaturated cyclohexenyl; hydrogenating the latter
compound by catalytic reduction in the presence of a
hydrogenation catalyst selected from the group consisting
of Raney nickel and palladium, thereby forming a com
pound having the formula
65
C 0 O-lower alkyl
l
0
70
wherein X has the same meaning indicated above, and
wherein each of X and R has the same meaning indicated
Z represents a member of the group consisting of lower
above; and hydrogenating the latter compound by cata
alkyl and cyclohexyl; and subjecting the latter compound
lytic reduction in the presence of a hydrogenation catalyst
to hydrolysis~decarboxy1ation by treating it with a hy
selected from the group consisting of Raney nickel and 75 drolysis reagent selected from the group consisting of
3,079,395
12
1.1
.rmineral acids'and alkaline lyes, thereby forming a com
pound having the formula
1,3 - dien - 1,4 - ylene; triGQWer-aIKQXy) - buta - 1,3 - dien
1,4-y1ene; and lower alkylenedioxy - buta - 1,3 - dien - 1,4
ylene; and Z represents a member of the group consisting
7-5
of lower alkyl and cyclohexyl.
7. A compound having the formula
10
wherein each of X and Z has the same meaning indicated
above.
_
5. A compound having theformula
15
wherein X represents a divalent radical selected from the
.group consisting of buta-1,3-dien-1,4—ylene; mono?ower
'alkoxyybuta-1,3-dien4;4-ylene;"‘di(lower alhoxy)-buta#1,3~
dien-1,4-y1ene; tri?ower a1koXy)-buta'-1,3-dien-1,4-ylene;
20
ll
and lower alkylenedioxy-buta-1,3-dien~1,4-y1ene.
8. 2-oxo-3-1ower carbalkoxy-9J0-di?ower alkoxy)—1,2,
3,4,6,7-hexahydro—1 1bH-benzo[a]quino1izine.
\0 0 Oslower slkyl
9. 2-oxo-3-(lower 2-a1ken-1-yD-3-1ower carbalkoxy)~9,
0
wherein X represents a divalent radical selected from the 25
group consisting of buta-1,3-dien11,4-y1ene; mono-(lower
alkoxy)-buta¢1,3-dien-1,4-y1ene; "di?ower alkoxy)-buta
I,3-dien-1,4-y1ene; tri(lower alkoxy)-buta-1,3-dien-1,4-yl
10-di(lower alkoxy)-1,2,3,4,‘6,7-heXahydro-11bH-benzo[a]
quinolizine.
10. 2 - 0x0 - 3 - lower a1ky1~3-lower carbalkoxy-9,10-di
(lower alkoxy)-1,2,3,4,6,7-heXahydro-11bH-benzo[a] quin
olizine.
11. 2-oXo-9,10-di(lower alkoxy)-1,2,3,4,6,7-hexahydro~
one; and lower alkylenedioxybuta-1;3-dien-l,4-y1ene; and
‘R‘represents-a member of the group'consisting of ?-un 30 >1 1bH-berizo[a]quino1izine.
saturated lower alkenyl, ,B-unsaturate'd lower‘ alkynyLand
References Cited in the ?le of this patent
UNITED STATES PATENTS
“?eunsaturated 'eyclohexenyl.
'6. 7A- compound ‘having the formula
-3
2,830,992
2,830,993
Brossi et a1 ___________ __ AprQlS, 1958
Brossi et al. __________ __ Apr. 15, 1958
789,789
iGreatBritahr- ________ __ Jan. 29,1958
FOREIGN PATENTS
40
C0 O-Iowef'alkyl
0
OTHER REFERENCES
Battersby et a1.: Experientia, vol. ‘#10 (1950), pages
wherein X represents a divalent radical selected from the
group consisting of buta’1';3-dien—1,4-ylene; mono?ower 4
378—9.
alkoxy)-buta-1,3-dien-1,4-ylene; di(l0wer alkoxyybu-ta
2470.
Battersby et aL: Iour. Chem. 800., 1953, pages 2463
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent ‘No. 3,079,395
February 26, 1963.‘
the above n
.
umbered pat
'
.
tha/t the said Letters
Patent
should
read as
corrected below.
Column 6, line 15, after “hour” insert
8, line 3, for "2" read ——
period; column
12, aline
42V - after
-— Brossi et al.>: Helv.
,
after
line
45, insert
(Feb, 1958) ,, -—.
Chim. Acta. , vol. #éllv pages 121-130
——; column
same 3 column
12
"vol. " lnsert —-- 6 ——;
Signed and sealed this 19th day of November 1963.
(SEAL)
Attest:
ERNEST v w°
SWIDER
Attesting Officer
V
_
"
“5333
EDWIN
.
.
Lu v_REYNOLDS
‘
Ac ting Commissioner of Patents
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