PROCEDE POUR LA PRODUCTION DE CYANURES DE BENZYLE SUBSTITUES

PROCESS FOR THE PRODUCTION OF SUBSTITUTED BENZYL CYANIDES

Abrégé anglais

INVENTORS
CTIRAD PODESVA
SILVIO IERA
TITLE
PROCESS FOR THE PRODUCTION OF
SUBSTITUTED BENZYL CYANIDES
ABSTRACT OF THE DISCLOSURE
The present invention provides a process for the
production of certain 3-lower alkoxy-4-hydroxybenzyl
cyanides in which process the anilino moiety of an N-phenyl-
3-lower alkoxy 4-hydroxybenzylamine is replaced with a
cyanide group by reaction with an alkali metal cyanide. The
substituted benzyl cyanides are useful intermediates in the
production of pharmacologically active substituted phenyl
acetic acid ester.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined
as follows:
1. A process for the production of 3-lower alkoxy-4-
hydroxy benzyl cyanides of the formula I:
<IMG> ......I
wherein R is lower alkyl;
comprising reacting an N-phenyl 3-lower-alkoxy-4-hydroxy-
benzylamine of formula II:
<IMG> .....II
with an alkali metal cyanide in a polar solvent.
2. Process according to claim 1 wherein the N-phenyl
3-lower alkoxy-4-hydroxybenzylamine of formula II is produced
by reducing a Schiff's base of formula IV:
<IMG> .......IV
11

wherein R is lower alkyl.
3. Process according to claim 2 wherein the Schiff's
base of formula IV is produced by reacting a compound of
formula III:
<IMG> ......III
wherein R is lower alkyl;
with aniline.
4. Process according to claim 1, 2 or 3 wherein the
solvent is an aprotic solvent.
5. Process according to claim 1, 2 or 3 wherein the
solvent is dimethylformamide.
6. Process as claimed in claim 1, 2 or 3 wherein the
reaction between the N-phenyl 3-lower-alkoxy-4-hydroxybenzyl-
amine and the alkali metal cyanide is effected under an
inert atmosphere.
7. Process as claimed in claim 1, 2 or 3 wherein the
reaction between the N phenyl 3-lower alkoxy-4-hydroxybenzyl-
amine and the alkali metal cyanide is effected under a
nitrogen atmosphere.
8. Process according to claim 1, 2 or 3 wherein the
alkali metal cyanide is potassium or sodium cyanide.
9. Process according to claim 2 or 3 wherein the Schiff's
base of formula IV is reduced by a metal hydride in an anhydrous
medium.
12

10. Process for the production of 3 methoxy-4-hydroxybenzyl
cyanide comprising reacting N-phenyl 3-methoxy-4-hydroxy-
benzylamine with an alkali metal cyanide in a polar solvent.
11. Process according to claim 10 wherein a Schiff's
base of formula IVa:
<IMG> .......IVa
is reduced to produce the N-phenyl-3-methoxy-4-hydroxybenzylamine.
12. Process according to claim 11 where the Schiff's
base of formula IVa is produced by reacting vanillin with
aniline.
13. Process according to claim 10, 11 or 12 wherein the
polar solvent is aprotic.
14. Process according to claim 10, 11 or 12 wherein the
polar solvent is dimethylformamide.
15. Process according to claim 10, 11 or 12 wherein the
reaction of vanillin with aniline is effected under an inert
atmosphere.
16. Process according to claim 10, 11 or 12 wherein the
reaction of vanillin with aniline is effected under a nitrogen
atmosphere.
17. Process according to claim 10, 11 or 12 wherein the
alkali metal cyanide is potassium cyanide.
13

18. Process according to claim 11 or 12 wherein the
Schiff's base is reduced with a metal hydride in an anhydrous
medium.
19. Process according to claim 11 or 12 wherein the
Schiff's base is reduced with sodium borohydride.
14

Description

6.30.5553 Can.
~067099
Field of Invention
=~ _
The present invention relates to the production of
substituted benzyl cyanides, in particular 3-lower alkoxy-4-
hydroxy-benzyl cyanides. These compounds are useful
intermediates in the production of valuable pharmacologically
active compounds, especially various substituted phenyl-
acetic acids, for example, those described in U.K. patent
No. 906,250 and Canadian patent No. 668,696. The best known
of these compounds at the present time is 3-methoxy-4-
N,N-diethylcarbamoylmethoxy-phenylacetic acid n-propyl ester,
commonly referred to as "propanidid". These compounds are
considered to be valuable agents for inducing narcosis; in
particular, the compounds are capable of inducing a signifi-
cant but relatively brief narcotizing effect which enables a
treated subject to make a rapid recovery.
Description of Prior Art
There are several known processes for producing
3-lower alkoxy-4-hydroxy benzyl cyanides of the general
formula:
HO ~ CH2CN ....................... I
OR
wher~ein R is lower alkyl having at most six carbon atoms.
Of particular importance in the present instance is 3-methoxy-
4-hydroxy benzyl cyanide which may be used as an intermediate
in the production of propanidid. For example, J.H. Short,
D.A. Dunnigan, C.W. Ours, Tetrahedron 29, 1931 (1073 et seq)
3~ teaches the reductive alkylation of vanillin according
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to the following scheme:
~0 ~ CH0 + CH3NH2 + H2 -- ~H ~ CH2NHCH3 + H20
CH30
C~30
110 - 130C ~ H0 ~ CHzCN + CH3NH2
CH30
In German Offenlegungsschrift 2,457,079 there is a
discussion of the above process and the disadvantages
associated therewith. In an attempt to overcome the
disadvantages, the applicant proposes a novel process
comprising reacting an N-alkyl benzylamine of formula:
.
H0 ~ CH2NHR
~ ~ OCH3
wherein R is alkyl, with hydrogen cyanide, either in free
form or prepared in situ from sodium cyanide, at a
temperature of 100-190C. However, this process also
leaves something to be desired since, inter alia, the use of
hydrogen cyanide~ in any form, is to be avoided if at all
possible.

1067099
Description of Invention
It has now been found that the desired 3-lower
alkoxy-4-hydroxy benzyl cyanides of fonmula I can be
prepared without the use of hydrogen cyanide (either free or
prepared in situ). More specifically it has now been found
that the anilino moiety of certain N-phenyl benzylaminescan
be converted to the desired nitri~e by reaction of the N-
phenyl benzylamlne with an alkali metal cyanide salt.
In one aspect, the present invention provides a
method for the production of 3-lower alkoxy-4-hydroxy benzyl
cyanides of the formula:
HO ~ CH2CN .......................... I
OR
by reacting an N-phenyl-3-lower alkoxy-4-hydroxy benzylamine
of formula II:
2C
HO ~ CH2NH ~ ......................... II
OR
wherein R is lower alkyl with an alkali metal cyanide in a
polar solvent.
After completion of the reaction, an agent,
usually a metal salt, which reacts with excess cyanide ions
to produce an insoluble cyanide, such as cadmium, cobalt and
nickel, salts, for example, the metal chlorides, especially
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1067(~99
zinc chloride is added to the reaction mixture, usually in
an aqueous solution, this resulting in the formation of an
insoluble cyanide precipitate which can easily and
conveniently be removed by simple filtration. The organic
phase remaining is, if necessary, dried and the organic
solvent removed by simple distillation at reduced pressure
to leave the desired product as an oil which subsequently
crystallizes to form a low melting point solid.
Suitable solvents include polar aprotic solvents
such as dimethyl formamide and especially dimethylsulphoxide.
Suitable alkyl metal cyanides are sodium and especially
potassium cyanide. The reaction may conveniently be effected
at a temperature of from 100-150C, especially from 120-
140C.
It has been found very advantageous to effect the
reaction between the amine and cyanide under an inert
atmosphere, such as nitrogen gas, this reducing or even
eliminating any undesirable tendencies of the benzylamine
reactant and displaced aniline to degrade.
In an especially preferred embodiment of the
present invention 4-hydroxy-3-methoxybenzyl cyanide is
produced by reacting N-phenylvanillylamine and potassium
cyanide in dimethylsulphoxide under a nitrogen atmosphere
at a temperature of from 100-150C, preferably 125-135C.
Subsequently the reaction mixture is treated with an
aqueous solution of a salt which forms an insoluble cyanide
such as zinc chloride, resulting in the cyanide being
precipitated. The precipitate is filtered off and the
organic solvent removed by distillation under reduced
pressure, giving the desired product being obtained as an

67U99
oil which subsequently solidifies to form a low melting
point solid.
The N-phenyl-3-lower alkoxy-4-hydroxy benzylamines
of formula II are known compounds and processes for their
production may be found in the literature. One very
convenient process for producing such compounds has been
found to be as follows:
HO ~ CHO + H2N ~ ............ III
R
H~--CH=N_~ , . . . IV
OR
HO ~ C~-N~ ~ .... II
The reduction of the Schiffs base of formula IV to the
desired N-phenylbenzylamine of formula II may be effected
by methods presently known in the literature and used in
the art. However, the reduction is rapidly and conveniently
carried out at below ambient temperatures with a metal
hydride such as sodium borohydride. Using this route
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1067(~99
alternative hydrogenation procedures using hydrogen and
expensive catalysts may thereby be avoided.
In a further aspect, the present invention
provides a process for the production of 3-lower alkoxy-4-
hydroxy benzyl cyanide of formula I wherein a Schiffs
base of formula IV:
HO ~ CH=N ~ ................................. IV
OR
wherein R is lower alkyl is reduced by a metal hydride to
form the corresponding N-phenyl benzyiamine of formula II:
which is subsequently converted using an alkali metal
cyanide in a polar solvent under an inert atmosphere as
described above into the desired benzylcyanide of formula I.
This process is very advantageous for producing
the preferred 3-methoxy-4-hydroxybenzyl cyanide since
vanillin, the starting material for the production of the
Schiffs base of formula IV is readily available at relatively
- low cost, generally lower for example than the corresponding
alcohol. Therefore, not only is the necessary starting
` material (vanillin) relatively inexpensive and the use of
hydrogen cyanide avoided, but the process affords very
high yields, conversion of N-phenylvanillylamine to 3-methoxy-
4-hydroxy benzyl cyanide and conversion of vanillin to N-
phenylvanillylamine occurring in yields approaching 90~
giving an overall yield for the multistep embodiment inherent
of the process of about 80~ from the readily available
vanillin.
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1067Q9g
It has not previously been ~nown to replace a substitued
amino group of formula -NHR with a cyanide group when R is
an aryl group. This provides several advantages: for example,
aniline is widely used and readily available at relatively
low cost; moreover, it has a high boiling point of 185C
which enables the intermediates of formula IV to be produced
in a simple liquid medium reaction at high temperatures
such as solvent reflux temperatures with virtually no loss
of aniline due to evaporation. Moreover, upon the aniline
moiety being displaced by the cyanide moiety the non-volatile
aniline produced is not lost but is easily recovered for
re-use in the process which not only reduces the operating
costs of the process but also reduces or eliminates a
potential pollution problem, an advantage which is growing
in importance as industry as a whole is being forced to
reduce the pollution it generates. In the prior art processes
discussed above, the displaced molecule is a lower mono
alkylamine which generally have relatively low boiling
points and high volatilities. For example, the methylamine
displaced in the pror art process as discussed above has a
boiling point of about -6C and hence, would not prove
recoverable and could not be re-used in the process.
.. . . . ........... . .
EXAMPLE 1
Preparation of N-Phenylvanillylamine
A mixture of 4.65 gm (0.05 mole) of aniline and
7.4 gm (0.5 mole) of vanillin in 37 ml of isopropylalcohol
(water oontent less than 0.2%) (by K.F.) were refluxed for
two hours. The resulting solution was cooled to 0-5C and
1.9 gm (0.05 mole) of sodiumborohydride was added in
portions over a period of 20 minutesl the temperature being
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:~Q67099
maintained during that period at 0-5C. The suspension
resulting was stirred for one hour at 0-5C following which
it was-allowed to warm to 20-25C over a period of one hour.
40 Ml of 20% v/v hydrochloric acid was added slowly at
20-25 in portions (to prevent foaming), the pH dropping to
1-2, following which 3S ml of ammonium hydroxide was added,
the Ph rising to 9.5-10. The alcohol was stripped from
the mixture under reduced pressure, the distillate being
arrested when water commenced to distill. To the oily
residue,15 ml of water and 100 ml of toluene were added,
,the organic phase separated, washed with brine and dried.
The toluene distilled off under reduced pressure leaving
9.8 gm (86% of theory) of the desired product as an oily
residue.
Preparation of 4-Hydroxy-3-MethoxYbenzylcYanide
A mixture of 1.86 gm (0.0286 mole) of potassium cyanide
and 6 gm (0.026 mole) of N-phenylvanillylamine in 30 ml of
dimethylsulfoxide were heated under nitrogen atmosphere
at an internal temperature of 125-130C for 19 hours. The
dimethylsulfoxide then removed under a reduced pressure (about
20-25 ml of mercury). The residue was cooled and 60 ml of
,, water added resulting in the formation of a dark solution.
0.2 Gm of Norit A*activated carbon was added and the mixture
stirred at a pH of about 11 for 30 minutes and then filtered.
A solution of 1.5 gm (0.0143 mole) of zinc chloride and 6 ml
of water was added dropwise to'the mixture at 20-25C, this
mixture was stirred for a further 20 minutes at a pH of 7,
30 ml of ethyl acetate then added to the suspension which was
stirred for a further 20 minutes. The precipitated zinc
cyanide was filtered off and the filter cake washed well with
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1~67099
ethyl acetate. The organic layer separated, washed with brine
and dried. Distillation of the ethyl acetate under reduced
pressure left 3.75 gm (88~ of theory) of crude 4-hydroxy-3-
methoxy-benzylcyanide as an oil, b.p.(0.2-0.3 mm Hg)
127-132C : redistillation of the oil gave a solid m.pt.
48-S0C.
It should be noted that although zinc cyanide is
a solid and relative to reagents such as hydrogen cyanide,
easily handled, it is a potentially dangerous compound
if ingested, inhaled or if it comes into
contact with the skin, therefore, normal precautions for
the utilization of such basic reagents should be used during
the filtration step.
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