PROCESS FOR THE MANUFACTURE OF 1,2-DISUBSTITUTED 1,2,3,4,5,6,7,8-OCTAHYDROISOQUINOLINES

PROCEDE POUR LA FABRICATION DE 1,2,3,4,5,6,7,8-OCTAHYDROISOQUINOLINES DISUBSTITUEES EN 1,2

English Abstract

Abstract
A process for the manufacture of the isoquinolines of
the formula
<IMG> (I)
wherein R is methyl or benzyl and R' is phenyl,
p-hydroxyphenyl or p-methoxyphenyl,
by reacting a solution of an enamine of the formula
<IMG> II
wherein R and R' have the above significance,
in a hydrocarbon with an anhydrous solution of p-toluene-
sulphonic acid in toluene or xylene at an elevated temper-
ature.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS
1. A process for the manufacture of the isoquinolines
of the formula
<IMG> I
wherein R is methyl or benzyl and R' is phenyl, p-
hydroxyphenyl or p-methoxyphenyl,
which process comprises reacting a solution of an enamine
of the formula
<IMG> II
wherein R and R' have the above significance,
in a hydrocarbon solvent with an anhydrous solution of p-
toluene-sulphonic acid in touluene or xylene at a
temperature between about 90° and 115°C.
2. A process according to claim 1, wherein R' is p-
methoxyphenyl, the hydrocarbon utilized is toluene or
xylene, and the reaction temperature amounts to about
110°C where R is methyl, and about 100°C where R is
benzyl.
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3. A process for the preparation of the isoquinolines
of formula I according to claim 1, which process comprises
(a) reacting a solution of an amine of the formula
<IMG>
III
wherein R is methyl or benzyl,
in toluene or xylene while heating with a solution of an
aldehyde of the formula R'CH2CHO, wherein R' is phenyl, p-
hydroxyphenyl or p-methoxyphenyl, in toluene or xylene, or
(b) reacting a solution of the amine III in a
hydrocarbon solvent, while heating with an ethereal
solution of the aldehyde R'CH2CHO, and,
(c) reacting the obtained enamine of formula II in
claim 1, in the manner set out in claim 1.
4. A process as in claim 3, wherein the hydrocarbon in
step (b) is an aliphatic hydrocarbon.
5. A process as in claim 4, wherein the aliphatic
hydrocarbon is n-hexane.
6. A process as in any one of claims 3, 4 or 5, wherein
the heating in step (b) is carried out under reduced
pressure.
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Description

R~N 4 o
The present invention is concerned with a process for
the manufacture of the isoquinolines of the formula
~)ÇN~R
R'
wherein R is methyl or benzyl and R' is phenyl,
p-hydroxyphenyl or p-methoxyphenyl,
2G which process comprises reacting a solution of an enamine
of the formula
,
l 11 1
~ N~R
~ II
R'
wherein R and R' have the above significance,
in a hydrocarbon with an anhydrous solution of p-toluene-
sulphonic acid in toluene or xylene at an elevated temper-
ature.
Aliphatic hydrocarbons such as n-hexane or, prefer-
ably, aromatic hydrocarbons such as toluene or xylene are
conveniently used as the hydrocarbon. The reaction is
conveniently carried out at between about 90 and 115C,
preferably at about 110C where R is methyl and at about
100C where R is benzyl.
Mé/13.1.88

~31~3~2
In addition to the isoquinoline of formula I there are
also obtained small amounts (4-7~) of the isomeric
isoquinolines of the formulae
~`R GÇ R ~`R
R' R' R'
la Ib Ic
wherein R and R' have the above significance.
If desired, these byproducts can be isomerized to the
isoquinolines of formula I, which can be carried out under
the same process conditions as in the case of the con-
version of the enamines of formula II into the
isoquinolines of formula I by reaction with p-toluene-
sulphonic acid.
The starting enamines of formula II can be prepared by
a) reacting a solution of an amine of the formula
~~
~J N~i
R III

~ 3 1 ~ 2
wherein R is methyl or benzyl,
in toluene or xylene while heating with a solution of an
aldehyde of the formula R~CH2CHO, wherein R~ is phenyl,
p-hydcophenyl or especially p-methoxyphenyl, in toluene or
xylene, or
b) reacting a solution of the amine III in a hydrocarbon.
especially an aliphatic hydrocarbon such as n-hexane,
while heating, optionally under reduced pressure, with an
ethereal solution of the aldehyde R'CH2CHO.-
As the hydrocarbon in process variant b) there can be
used one which is suitable for the conversion of a
compound of formula II into a compound of formula I,
preferably n-hexane. Water and toluene or xylene are
distilled off in process vaeiant a) and water and ether
are distilled off in process variant b).
The solution of the aldehyde R'CHzCHO in toluene or
xylene, which i6 used in process variant a), can be
obtained by heating to reflux temperature a suspension of
an alkali metal salt or alkaline earth metal salt of the
corresponding glycidic acid of the formula
R'CH-CHCOOH
o IV
preferably potassium glycidate, in toluene or xylene in
the presence of aqueous acetic acid. The ethereal aldehyde
solution which is used in process variant b) can be
obtained by treating a suspension of a sulphonate of the
formula
~ OH
R'CH2CH ~
OS02Na V

~ 3 ~
in aqueous diethyl ether in the presence of potassium
carbonate at a tem~erature of abou~ 1-3C.
The compounds of formula I can be converted into
morphinans such as dextromethorphan as described e.g.
in United States Patent 3,634,429 and Chemical Abstracts
51 (1957) 2876f.
Example 1
a) 70 ml of an aqueous solution of 3.64 g of ace~ic acid
are added dropwise to a mixture, heated to the boiling
point, of 14 g (59 mmol) of potassium (E)-a,~-epoxy-p-
-methoxycinnamate, 112 ml of toluene and 28 ml of water.
After 5 minutes the mixture is cooled to room temperature.
The organic phase is washed with water and then with
aqueous potassium carbonate solution. The aqueous washings
2G are extracted with toluene. The organic ehase is dried
azeotropically. The yield of p-methoxyphenylacetaldehyde
in the solution obtained amounts to 92-94~.
b) The solution of p-methoxyphenylacetaldehyde in 200 ml
of toluene, prepared according to Example la), is added
under reflux within one hour to a mixture of 78 g
(55.5 mmol) of N-methyl-2-(cyclohexen-1-yl)ethylamine in
20 ml of toluene. After 1 hour under reflux there is
obtained N-[(E)-p-methoxystyryl]-N-methyl-2-tcyclohexen-1-
-yl)ethylamine (yield 95.3%) dissolved in toluene.
c) The solution prepared according to Example lb) is
added to a solution of dry p-toluenesulphonic acid
(corresponding to 60 g of monohydrate) in 600 ml of
toluene. After heating under reflux for 3 hours the mix-
ture is cooled and made alkaline with 40% sodium hydroxide
solution. After extraction with toluene, washing with
water and concentration of the organic phase there is
obtained an oil which is distilled at 190C under 1 mbar.

There are obtained 13.6 g of a clear oil with a content of
1-(p-methoxybenzyl)-Z-methyl-1,2,3,4,5,6,7,8-octahydro-
isoquinoline of 90.8% (yield 83%) and a content of the
isomers l-(p-methoxybenzyl)-2-methyl-1,2,3,4,6,7,8,8a-
-octahydroisoquinoline, l-(p-methoxybenzyl)-2-methyl-
-1,2,3,4,4a,5,6,7-octahydroisoquinoline and l-(p-
-methoxybenzyl)-2-methyl-1,2,3,5,6,7,8,8a-octahydro-
isoquinoline of all together 5%.
~ d) 16.3 g of oxalate are precipitated by means of 4.5 g
of oxalic acid in 190 ml of acetone. The mixture of
isomeric isoquinolines isolated from the mother liquor is
isomerized to a large part to l-(p-methoxybenzyl)-2-
-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline by treatment
with p-toluenesulphonic acid as described in Example lc).
0.66 g of oxalate is obtained from this mixture by again
precipitating with 0.56 g of oxalic acid in 15 ml of
acetone. Afte~ liberation of the oxalate there are
obtained 12.7 g (yield 83.5% based on the starting amine)
of more than 99% pure 1-(p-methoxybenzyl)-2-methyl-
-1,2,3,4,5,6,7,8-isoquinoline.
ExamPle 2
a) 16.8 ml of an aqueous solution of 10 g of potassium
carbonate are added within 5 minutes to a mixture, cooled
to 1-3C, of 8.2 g (33 mmol) of sodium 1-hydroxy-2-(p-
-methoxyphenyl)ethylsulphonate, 8.4 ml of water and 84 ml
of diethyl ether. The mixture is left to warm to room
temperature for 1 hour and L26 ml of water are then added.
The organic phase is washed with water and the aqueous
phase is washed with ether. The organic phase is then
dried over sodium sulphate. The yield of p-methoxyphenyl-
acetaldehyde amounts to 57%.

b) The 125 ml of the ethereal p-methoxyphenylacetaldehyde
solution prepared according to Example 2a) are added
slowly to a solution of 3.48 g (16 mmol) of N-benzyl-2-
-(cyclohexen-l-yl)ethylamine in hexane at 50~C. The react-
ion water and the ether are distilled off. ~fter reaction
for 4 hours the resulting solution of N-benzyl-2-(cyclo-
hexen-l-yl)-N-r(E)-p-methoxystyryl]ethylamine is added at
100C to a solution of 36 g of p-toluenesulphonic acid in
250 ml of toluene. After reaction for 2 hours the mixture
is cooled and made alkaline with sodium hyd~oxide solu-
tion. The organic phase is washed with water. The aqueous
phase is extracted with toluene. The organic phase is
dried over sodium sulphate, filtered and evaporated. There
are obtained 5.72 g of an oil with a content of 2-benzyl-
-l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
of 76.5%. Yield 79% based on the starting amine.
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