Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~3~
The invention relates to a novel process for the
preparation of phenylether compounds having the general
formula (I),
- CH2 - IH C~3 (I)
CH3 A
wherein A stands for hydroxy, acyloxy, alkylsulfonyloxy,
arylsulfonyloxy, azido or amino group, and pharmaceutically
acceptable salts thereof.
The compounds of the general formula (I), wherein A
stands for amino or hydroxy group, are known from the
literature, whereas the further derivatives are novel.
The compounds of the general formula (I) possess
valuabl~ biological activities, furthermore some of them can
also be applied as key intermediates in the synthesis of other
compounds having the general formula (I).
Thus e.g. 1-(2,6-dimethylphenoxy)-2 amino-propane
(formula (I), A = amino) and its pharmaceutically acceptable
acid addition salts exert beneficial effects in ventricular
arrhythmic states, and can be applied to advantage particularly
in the therapy of ischaemic cardial disorders, myocardial
infarcts, ventricular fibrillation and tachycardia ~Brit. Heart
J. 35, 558, 559 (1973); Lancet 1973/II, 339-403, 404-407;
Brit. J. Clin. Pharmacol. 1, 86-87, 229-232 (1974) ). The new
compound of the general formula (I), wherein A stands for azido
group, has similar pharmacological effects.
Several methods are disclosed in the sritish patent
specification No. 1,205,958 for the preparation of 1-(2,6-
dimethylphenoxy)-2-amino-propane. According to one of these
methods the aimed product is prepared by removing the protecting
-- 2 --
113259~3
group(s) of a compound of the general formula (II),
~ O CH2 IC CH3 (II)
CH3 B
wherein B is an amino group having one or two protecting
groups. Benzyl, phthalyl, toluenesulfonyl and formyl groups
are mentioned in the cited reference as protecting groups, the
working examples relate, however, only to the splitting of the
benzyl group.
The starting substances of the general formula (II)
can be prepared according to the above British patent specifi-
cation by reacting a compound of the general formula (III),
CH3
O - CH2 - CH - CH3 (III)
CH3 Hal
wherein Hal stands for a halogen atom, with a compound of the
general formula (IV),
B - H (IV)
wherein B is as defined above.
The compounds of the general formula (II) can also
be prepared by reacting a ketone of the formula (V)
, CH3
O - CH2 - 1I CH3 (V)
CH3
with a compound of the general formula (VI),
~ - 3 -
1~3Z59~3
H2N - Q (VI)
wherein Q stands for the protecting group present in
substituent B, under reductive conditions (British patent
specificat;on No. 1,205~958).
The above method has the following disadvantages:
The hydrogenation of the compounds haviny the general
formula (II), wherein the protecting group is benzyl, proceeds
only at 80C under a pressure of minimum 5 atmospheres, and
yields the desired amino compound with a medium yield (about
50 to 55~).
Furthermore, the starting substances themselves are
difficult to prepare. When the compounds of the general
formula (II) are prepared by reacting a compound of the general
formula (III) with a compound of the general formula (IV),
double alkylation also takes place owing to the high reactivity
of benzylamine, resulting in the formation of a bis derivative
of the formula (VII)
CH3
O - CH - CH - CH
CH3 N - CH2 ~ (VII)
CH3
O CH - CH - CH
CH3
as by-product. Moreover, the reaction proceediny with the
excess of the amine involves hydrohalide elimination, leading
to the formation of additional by-products. The products
themselves are difficult to purify, which further decreases the
yield.
The compounds of the general formula (II) can also
be prepared by reacting a ketone of the formula (V) with an
appropriately protected amine under reductive conditions. This
-- 4 --
~13~S~3
method is, however, not exemplified in the cited patent
specification.
Additional difficulties arise in the preparation of
the formula (V) ketone itself, since this compound is
synthetized by reacting a salt of 2,6-dimethylphenol with
chloroacetone or bromoacetonej which are highly poisonous
substances (N.I. Sax: Handbook of Dangerous Materials,
Reinhold Publ. Corp., New York, 1951, page 94).
The British patent specification No. 1,205,958 also
mentions the utilization of phthalyl, toluenesulfonyl and
formyl protecting groups, these methods being, however, not
illustrated by examples.
According to a further method disclosed in the
British patent specification No. 1,205,958 the ketone of the
formula (V) is treated first with ammonia, hydroxylamine or
hydrazine, and the resulting compound of the general formula
(VIII),
2 ICl CH3 (VIII)
CH3 N
wherein Y stands for hydrogen, hydroxy or amino, is reduced
either by catalytic hydrogenation or with an appropriate
complex metal hydride to obtain l-(2,6-dimethylphenoxy)-2-
amino-propane.
This method, again, has several disadvantages. The
hydrogenation can be performed only with moderate yields
(51.5% for the oxime and 44.3% for the imine; no example is
ll~Z5~8
given for the reduction of the hydrazone), furthermore, as
discussed above, the starting ketone of the formula (V) is
difficult to prepare.
According to a further method disclosed in the above
British patent specification, 1-(2,6-dimethylphenoxy)-2-amino-
propane can be prepared directly from 2,6-dimethylphenol by
reacting it with l-methyl aziridine. No example is given,
however, in the specification for this method.
The disadvantage of this method resides in the use
of l-methyl-aziridine. This compound, like ethyleneimine, is
extremely poisonous (see N.I. Sax: Handbook of Dangerous
Materials, Reinhold Publ. Corp., New York, 1951, page 328),
furthermore it is highly liable to polymerization. The
polymerization sets in even when heating the mixture or upon
the effect of trace amounts of acids (such as phenol)~
A still further method disclosed in the British
patent specification No. 1,205,958 applies a salt of 2,6-
dimethylphenol as starting substance. The salt is reacted with
a compound of the general formula (IX),
Z - CH2 - CH - CH
IH2 (IX)
wherein Z is a reactive ester group, such as halogen. This
method is not exemplified, either.
The disadvantage of this method resides in the use
of the formula (IX) reactants, since they are difficult to
prepare and undergo dimerization rather easily, forming thereby
piperazine derivatives.
1-(2,6-Dimethylphenoxy)-2 hydroxy-propane is mentioned
in the United States patent specification No. 3,979,460 as an
undesired by-product, which forms with a yield of 12% in the
synthesis
~13~5C~8
of 4,4'-hydroxy-3,3~-tetramethyl-diphenylsulfide. This patent specification
does not give the physical constants of the hydroxy compound.
Now it has been found that the compounds of the general formula
(I), wherein A is as defined above, can be prepared easily and with high
yields according to the following method:
2,6-Dimethylphenol is reacted with propylene oxide in an alkaline
medium, and, if desired, the resulting compound is acylated and, if desired,
the resulting compound of the general formula (I), wherein A is an acyloxy,
alkylsulfonyloxy or arylsulfonyloxy group, is reacted with an alkali metal
azide. If the respective amino compound is to be prepared, the resulting
1-(2,6-dimethylphenoxy)-2-azido-propane is reduced. This latter compound
can be converted into its acid addition salts.
Thus, the invention provides a process for the preparation of a
compound of the general formula (I),
~ - C~12 - CH - CH3 (1)
A
CH3
wherein A stands for hydroxy, acyloxy, alkylsulfonyloxy, arylsulfonyloxy,
azido or amino group, or an acid addition salt thereof, characterized by
reacting 2,6-dimethylphenol with propylene oxide in an alkaline medium and,
if required, acylating the resulting compound of the general formula (I),
wherein A is hydroxy, and, if required, reacting the resulting compound
of the general formula (I), wherein A is acyloxy, alkylsulfonyloxy or
arylsulfonyloxy, with an alkali metal azide and, if required, reducing the
resulting compound of the general formula (I), wherein A is azido, and, if
required, converting the resulting compound of the general formula (I),
wherein A is amino, into its acid addition salt.
In a prefered embodiment this invention provides a process for
the preparation of a compound of the general formula I
113Z5~
wherein A stands for an acyloxy, alkylsulfonyloxy, arylsulfonyloxy or azido
group, which comprises acylating a compound of formula
CH3
0-CH2-CH-CH3
CH3 OH
prepared by reacting 2,6-dimethylphenol with propylene oxide in an alkaline
medium with an acyl halide, alkylsulfonyl halide or arylsulfonyl halide to
obtain a product of formula I in which A stands for an acyloxy, alkyl~
- sulfonyloxy or arylsulfonyloxy group and, if a compound of formula I in
which A is an azido group is required, reacting the product with an alkali
metal azide.
This invention also provides for compounds of the general
formula(I) wherein A stands for acyloxy, alkylsulfonyloxy, arylsulfonyloxy
or an azido group.
Our experiences have shown that 1-(2,6-dimethylphenoxy)-2-
hydroxy-propane can be prepared easily and with a good yield by adding an
excessive amount of propylene oxide and a water-soluble organic solvent to
an aqueous alkaline solu~ion of 2,6-dimethylphenol, and stirring the result-
ing mixture under heating. It is preferred to apply sodium hydroxide or
potassium hydroxide as alkaline agent, since they form soluble phenolates
with the starting substance. Generally 1.05 to 10 moles of an alkali are
applied for one mole of 2,6-dimethylphenol. As water-soluble organic
solvent a lower alcohol or ketone, acetonitrile, tetrahydrofuran or dioxane,
preferably ethanol or acetone can be utilized. The reaction can be performed
at temperatures from 2QC to the boiling point of the reaction
'"" ~;
- 7a -
1~3Z598
mixture, preferably at 50 to 60C. If desired, the crude
1-(2,6-dimethylphenoxy)-2-hydroxy-propane, obtained after the
processing of the reaction mixture, can be applied directly
for the preparation of those compounds of the general formula
(I), wherein A represents an acyloxy, alkylsulfonyloxy or
arylsulfonyloxy group.
The terms "acyloxy", "alkylsulfonyloxy" and
"Arylsulfonyloxy" are applied in the specification in the
broadest sense, i.e. they encompass all groups derived by
subtracting a hydrogen atom from a carboxylic acid, alkyl-
sulfonic acid and arylsulfonic acid. The hydrocarbyl moieties
of these groups may be substituted by one or more groups, such
as halogen atoms, alkyl groups, etc.
1-(2,6-Dimethylphenoxy)-2-hydroxy-propane can be
converted into the respective acyloxy, alkylsulfonyloxy or
arylsulfonyloxy derivatives by conventional acylation methods
(see Houben-Weyl: Methoden der organischen Chemie, Georg
Thieme Verlag, 1952, Vol. 8, page 543).
Acylation is performed preferably in pyridine or in
a mixture cf dichloroethane and triethylamine, at a temperature
below 10C. The acylated compounds are formed in highly pure
state with excellent yields (over 98~). If desired, the acyl
derivatives can be applied directly for the preparation of
1-(2,6-dimethylphenoxy)-2-azido-propane (formula (I), A =
azido).
The azido compound is prepared by reacting a compound
of the general formula (I), wherein A is acyloxy, alkyl-
sulfonyloxy or arylsulfonyloxy group, with a metal azide,
preferably sodium azide, in the presence of water and a water-
soluble organic solvent, preferably ethyleneglycol monomethylether or ethyleneglycol monoethyl ether. The resulting
1-(2,6-dimethylphenoxy)-2-azido-propane is surprisingly stable
~ - 8 -
113~S~3
(it can be distilled and does not decompose even when heated
to 200C), and is being formed with good yields (83 to 89%).
If desired, this compound can be applied directly, without any
further purification, for the preparation of the respective
amino derivative.
The amino compound, i.e. 1-(2,6-dimethylphenoxy)-2-
amino-propane, is prepared by reducing the respective azido
derivative in a manner known per se (see Houben-Weyl: Methoden
der organischen Chemie, Georg Thieme Verlag, 1957, Vol. 11/1,
pages 262, 539 and 1002). Reduction is performed preferably
by catalytic hydrogenation.
In this latter reaction 1-(2,6-dimethylphenoxy)-2-
amino-propane base is obtained as the sole product, free of any
by-products, with an almost quantitative yield. The reaction
can be monitored easily by thin layer chromatography. The
reaction is easy to perform and does not require any specific
equipment.
The new process according to the invention provides
the following main advantages:
1) All of the starting substances are easy to prepare
and handle and are not deleterious to health.
2) The reactions can be performed easily without utiliz-
ing any specific equipment, and run with excellent yields.
3) All of the compounds of the general formula (I) are
stable substances easy to handle, and, even in crude state, are
sufficiently pure to subject them to further conversions.
4) The reduction of 1-(2,6-dimethylphenoxy)-2-azido-
propane to the respective amine can be performed at room
temperature under atmospheric pressure with an almost
quantitative yield, and a pure compound is produced.
11~325~3~
5) 1-(2,6-Dimethylphenoxy)-2-amino-propane can be
separated from the reaction mixture very easily.
The invention is elucidated in detail by the aid of
the following non-limiting Examples.
Example 1
1-(2,6-Dimethylphenoxy?-2-hydroxy-propane
12.2 g (0.1 moles) of 2,6-dimethylphenol are
dissolved in a solution of 4.2 g (0.105 moles) of sodium
hydroxide in 20 ml of water. 25 ml of ethanol and 8.7 g (0.15
moles) of propylene oxide are added to the solution, and the
mixture is stirred at 60C for 12 hours. The mixture is cooled,
200 ml of benzene and 200 ml of water are added, and the
organic phase is separated. The aqueous phase is extracted
with 200 ml of benzene. The benzene solutions are combined
washed with 200 ml of water, dried over sodium sulfate, and
evaporated to dryness in vacuo (40 mm Hg) from a steam bath.
14.6 g (81%) of an oily substance are obtained. This crude
product can be applied directly in the acylation reactions
described in Examples 2 to 5. The crude 1-(2,6-dimethyl-
phenoxy)-2-hydroxy-propane can be purified by distillation;
b.p.: 840C/Rf = 0.6 (chromatography on Merck grade silica gel
layer of 0.1 to 0.3 mm thickness in a 6:1 mixture of benzene
and pyridine; development with o-toluidine after chlorination;
see also Z. Anal. Chem. 1 ; 181 (1955) ).
Analysis:
calculated for CllH162 (m-wt- = 180-24)
C: 73.30%, H: 8.95%;
found: C: 73.60~, H: 9.07%.
-- 10 --
1~325~3
Example 2
1-(2,6-Dime~ phenoxy)-2-(4-methylphen
sulfonyloxy)-propane
.. . .
9.0 g (0.05 moles) of crude 1-(2,6-dimethylphenoxy)-
2-hydroxy-propane, obtained as described in Example 1, are
dissolved in 50 ml of dry pyridine, and 19.0 g (0.1 moles) of
tosyl chloride are added to the solution in small portions
under cooling with ice. During the addition the temperature
of the mixture should be maintained below 10 C. When the
addition is complete the cooling bath is removed, the mixture
is allowed to warm to 20 to 25C, and stirred for 1 hour at
this temperature. At the end of the reaction the mixture is
poured onto 100 g of crushed ice, and the product is extracted
with 200 ml of benzene. The benzene solution is washed with
water, dried over sodium sulfate, and evaporated to dryness in
vacuo. The obtained crystalline residue is recrystallized from
20 ml of isopropanol to yield 16.5 g (98.7%) of 1-(2,6-dimethyl-
phenoxy)-2-(4-methylphenylsulfonyloxy)-propane; m.p.: 63-64C.
The crude product, melting at 59-61C, can be applied directly
in the reaction described in Example 6.
Rf = 0.8 (chromatography on Merck grade silica gel
layer of 0.1 to 0.3 mm thickness in a 6:1 mixture of benzene
and pyridine; development with o-toluidine after chlorination).
Analysis:
calculated for C18H22S4 (m-wt- 334-42)
C: 64.64%, H: 6.63%, S: 9.59%;
found: C: 64.84%, H: 6.86%, S: 9.86%.
Example 3
1-(2,6-Dimethylphenoxy)-2-met a esulfonyloxy-propane
One proceeds as described in Example 2 with the
difference that 11.4 g (0.1 moles) of mesyl chloride are
~ .' - 11 -
~1~25~3
dropped into the pyridine solution of 1~(2,6-dimethylphenoxy)-
2-hydroxy-propane. The reaction mixture is processed as
described in Example 2 to yield 12.8 g (99.1%) of 1-(2,6-
dimethylphenoxy)-2-methanesulfonyloxy-propane as a honey-like
viscous substance. This crude product can be applied directly
in the reaction described in Example 7.
Rf = 0.8 (chromatography on Merck grade silica gel
layer of 0.1 to 0.3 mm thickness in a 6:1 mixture of benzene
and pyridine; development with o-toluidine after chlorination).
Analysis:
calculated for C12H184S (m-wt- 258.33):
C: 55.78%, H: 7.02%, S: 12.41%;
found: C: 56.20%, H: 7.52%, S: 12.14%.
Example 4
1-(2,6-Dimethylphenoxy-)-2-trichloroacetyloxy-propane
One proceeds as described in Example 2 with the
difference that 18.1 g (0.1 moles) of trichloroacetyl chloride
are dropped into the pyridine solution of 1~(2,6-dimethyl-
phenoxy)-2-hydroxy-propane. The reaction mixture is pro~essed
as described in Example 2 to yield 16.1 g (98.9%) of crude,
oily l-(2,6-dimethylphenoxy)-2-trichloroacetyloxy-propane,
which can be applied without purification in the process
described in Example 8. The product can be purified by
distillation; b.p.: 146C/0.4 mm Hg.
Rf = 0.85 (chromatography on Mercke grade silica gel
layer of 0.1 to 0.3 mm thickness in a 6:1 mixture of benzene
and pyridine; development with o-toluidine after chlorination).
Analysis:
calculated for C13H15C13O3 (m.wt.: 325.62):
C: 47.95%, H: 4.64%, Cl: 32.67%;
found: C: 48.12%, H: 4.92%, Cl: 32,48%.
1~3259~
Example 5
1-(2,6-Dimethylphenoxy)-2-(4-methyl-
phenylsulfonyloxy)-propane
11.1 g (0.11 moles) of triethylamine are added to a
solution of 9.0 g (0.05 moles) of crude 1-(2,6-dimethylphenoxy)-
2-hydroxy-propane, obtained as described in Example 1, in 100 ml
of dry dichloroethane. The solution is stirred under ice
cooling, and a solution of 19.0 g (0.1 moles) of tosyl chloride
in 50 ml of dry dichloroethane is added dropwise. When the
addition is complete the cooling bath is removed, the reaction
mixture is allowed to warm to 20 to 25C, and stirred for one
hour at this temperature. At the end of the reaction the
mixture is decomposed with 100 g of crushed ice, and the phases
are separated from each other. The dichloroethane layer is
washed with water, dried over sodium su~fate and evaporated to
dryness in vacuo. The crystalline residue is recrystallized
as described in Example 2 to obtain 16.55 g (98.9~) of
1-(2,6-dimethylphenoxy)-2-(4-methyl-phenylsulfonyloxy)-propane;
m.p.: 58-61C. This compound is identical with the product
obtained according to Example 2, and can be applied directly
in the reaction described in Example 6.
Example 6
1-(2,6-Dimethylphenoxy)-2-azido-~ropane
-
8.36 g (0.025 moles) of crude 1-(2,6-dimethylphenoxy)-
2-(4-methyl-phenylsulfonyloxy)-propane, prepared as described
in Example 2 or 5, are dissolved in 50 ml of ethyleneglycol
monomethyl ether. A solution of 3.25 g (0.05 moles) of sodium
azide in 15 ml of water is added in a single portion, and the
resulting mixture is refluxed for 5 hours. The mixture is
allowed to cool, admixed with 100 ml of water and 100 ml of
chloroform, and the organic phase is separated. The chloroform
solution is washed with 200 ml of water, dried over sodium
~ - 13 -
1132598
sulfate, and evaporated to dryness in vacuo (40 to 60 mm Hg)
over a steam bath. 4.6 g (89.6%) of crude 1-(2,6-dimethyl~
phenoxy)-2-azido-propane are obtained, which can be applied
directly in the reaction described in Example 9. The product
can be purified by distillation; b.p.: 106C/0.7 mm Hg.
Rf = 0.75 (chromatography on Merck grade silica gel
layer of 0.1 to 0.3 mm thickness in a 6:1 mixture of benzene
and pyridine; development with o-toluidine after chlorination).
Analysis:
calculated for CllH15N3O (m.wt.: 205-
C: 64.37%, H: 7.37%, N: 20.47%;
found: C: 64.65%, H: 7.48%, N: 20.30%.
Example 7
1-(2,6-Dimethylphenoxy)-2-azido-propane
One proceeds as described in Example 6 with the
difference that 6.46 g (0.025 moles) of crude 1-(2,6-dimethyl-
phenoxy)-2-methanesulfonyloxy-propane, obtained as described
in Example 3, is applied as starting substance, instead of
1-(2,6-dimethylphenoxy)-2-(4-methyl-phenylsulfonyloxy)-propane.
The reaction mixture is processed as described in Example 6 to
obtain 4.3 g (83.8%) of crude 1-(2,6-dimethylphenoxy)-2-azido-
propane, identical with the product obtained according to
Example 6.
Example 8
1-(2,6-Dimethylphenoxy)-2-azido-propane
One proceeds as described in Example 6 with the
difference that 8.14 g (0.025 moles) of crude 1-(2,6-dimethyl-
phenoxy)-2-trichloroacetyl-propane, obtained as described in
Example 4, is applied as starting substance, instead of
1-(2,6-dimethylphenoxy)-2-(4-methyl-phenylsulfonyloxy)-propane.
l'he reaction mixture is processed as described in Example 6 to
obtain 4.5 g (87.7%) of crude 1-(2,6-dimethylphenoxy)-2-azido-
- 14 -
~L13;25~
propane, identical with the product obtained according to
Example 6.
Example 9
_-(2,6-Dime_hylphenoxy) 2-amino-propane hydrochloride
1 g of palladium-on-charcoal catalyst is added to a
solution of 4.1 g (0.02 moles) of crude 1-(2,6-dimethylphenoxy)-
2-azido-propane, prepared according to any of Examples 6 to 8,
in 100 ml of ethanol. Hydrogen is bubbled slowly and
continuously through the flask, and the mixture is hydrogenated
under shaking at 20 to 25C for 5 hours. The progress of the
reaction is monitored by chromatography on Merck grade silica
gel layer of 0.1 to 0.3 mm thickness in a 6:1 mixture of benzene
and pyridine. The spots are developed with o-toluidine after
chlorination.
At the end of the reaction the catalyst is removed
by filtration and washed with a small amount of 70% aqueous
ethanol. The filtrate is acidified to pH = 1 with concentrated
hydrochloric acid and then evaporated to dryness in vacuo
(40 mm Hg~ over steam bath. The resulting 4.4 g (100%) of
crude, crystalline 1-(2,6-dimethylphenoxy)-2-amino-propane
hydrochloride are dissolved in 10 ml of isopropanol under
heating, the solution is filtered, and 50 ml of dry ether are
added to the filtrate at about 40C, whereupon the product soon
starts to crystallize. The mixture is cooled with ice, the
crystals are filtered off, washed with a small amount of ether
and dried. The resulting pure 1-(2,6-dimethylphenoxy)-2-amino-
propane hydrochloride melts at 201-203C.
- 15 -
