Note: Descriptions are shown in the official language in which they were submitted.
CA 02314988 2000-06-15
WO 99/32430 _ PCT/SE98/02315
PROCESS FOR THE PREPARATION OF ISOPROPYL-METHYL-[2-(3-N-
PROPOXYPHENOXY)ETHYL]AMINE
Field of the invention
The present invention relates to a novel process for the synthesis of
isopropyl-methyl-[2-(3-
n-propoxyphenoxy)ethyl]amine. Moreover, the present invention also relates to
a novel
intermediate and an optional purification step in said process. Additionally,
the present
invention also relates to the manufacture of a pharmaceutical formulation
containing
io isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine and the use of
isopropyl-methyl-[2-
(3-n-propoxyphenoxy)ethyl]amine in medicine.
Background of the invention and prior art
is Isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amineis a compound with
anaesthetic
properties. It is useful as a topical local anaesthetic for the treatment of
pain, including
localised pain, and especially on intact skin.
WO 9715548 discloses a process for the preparation of isopropyl-methyl-[2-(3-n-
propoxy
zo phenoxy)ethyl]amine. Said process comprises a couple of reaction steps
starting with
reacting 3-n-propoxyphenol with 1,2-dibromoethane resulting in 1-(2-
bromoethoxy)-3-n-
propoxybenzene. Further, 1-(2-bromoethoxy)-3-n-propoxybenzene is reacted with
N-
methylisopropylamine in an autoclave. The product, isopropyl-methyl-[2-(3-n-
propoxy
phenoxy)ethyl]amine, was thereafter further purified by distillation in vacuo.
Summary of the Invention
The object of the present invention is to provide a new process for the
preparation of
isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine suitable for full scale
production.
CA 02314988 2000-06-15
WO 99/32430 - PCTISE98/02315
2
Scheme 1 below describes the main reaction steps in the manufacture of
isopropyl-methyl-
[2-(3-n-propoxyphenoxy)ethyl]amine starting from 3-propoxyphenol. The starting
material
as well as the reactants used, are readily available through processes known
in the art.
s
Scheme I
Step 1
~o off Ethylene carbonate, ~o~o~oH
solid-liquid phase-transfer
catalysis
Step 2
OOH ~O \ ~ O~X
halogenating or
sulphonating reagent
~1) C2)
X ~ halogen or sulphonate ester
to
Step 3
o~ Isopropylamine ~o ~ ( o~NH
X
~2) ~3)
X = halogen or suiphonate ester
CA 02314988 2000-06-15
WO 99/32430 _ PCTISE98/02315
3
Step 4
~o ~ off, Formaldehyde, HZ o~o~i
metal catalyst
L3) ~4)
Advantages of the improved process of the present invention are disclosed in
the following
paragraphs.
s Another object of the present invention is to provide a process utilizing
reagents and
solvents that are environmentally friendly. There is a general interest from
environmental
groups both inside and outside the pharmaceutical industry that the industry
shall develop
and use environmentally friendly processes. The process of the present
invention does not
use any mutagenic alkylating agents, such as 1,2-dibromoethane, which is used
in
io processes according to prior art. One object of the present invention is
therefore to provide
a process for the manufacture of isopropyl-methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine
wherein the use of 1,2-dibromoethane is avoided. 1,2-dibromoethane is a known
mutagenic
compound and its use should therefore, if possible, be limited. This is
especially true in full
scale production.
Is
Another object of the present invention is to provide a new and optional
purification of
crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine. We have
surprisingly found
that the monophosphate salt of isopropyl-methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine is a
crystalline compound. The optional purifaction step is shown in Scheme 2.
CA 02314988 2000-06-15
WO 99/32430 _ PCT/SE98/02315
4
Scheme 2
H3POa
~x H3P04
(4) Base (5)
s In Step 1, 3-propoxy-phenol is reacted with ethylene carbonate using solid-
liquid phase-
transfer catalysis conditions. The reaction is preferably carried out at 60-
120'C and for a
prolonged period of time. The reaction is preferably carried out in an organic
solvent, such
as an aprotic organic solvent or xylene. Examples of such aprotic organic
solvents include,
but are not limited to, DMF, and 1-methyl-2-pyrrolidinone. 1-Metyl-2-
pyrrolidinone is the
io preferred aprotic organic solvent. Optionally, the reaction is carried out
without any
additional organic solvent. The amount of ethylene carbonate used is 1-4 molar
equivalents, preferably 2-3 equivalents. The solid-liquid phase-transfer
catalysis conditions
are created using a solid, non-soluble base and a phase-transfer catalyst. The
amount of
base and phase-transfer catalyst are not crucial and can therefore be varied
according to
is procedures known in the art. The base and the phase-transfer catalyst can
be any suitable
base and phase-transfer catalyst known in the art to create solid-liquid phase-
transfer
catalysis conditions. Examples of suitable bases include, but are not limited
to, sodium
carbonate, sodium hydrogencarbonate, potassium carbonate and potassium
hydrogencarbonate. Potassium carbonate is the preferred base. Examples of
suitable phase-
zo transfer catalysts include, but are not limited to, tetrabutyl ammonium
iodide, tetrabutyl
ammonium hydrogensulphate, and tetrabutyl ammonium bromide. Tetrabutyl
ammonium
bromide is the preferred phase-transfer catalyst.
The phase-transfer catalyst used in step 1, can be replaced by a compound
which has as an
2s intrinsic property to function as a phase-transfer catalysts under the
conditions used in Step
CA 02314988 2000-06-15
WO 99/32430 _ PCT/SE98/02315
1. . Examples of such compounds include, but are not limited to,
polyethyleneglycol
(PEG), e.g. PEG 6000.
After complete reaction, the reaction mixture is cooled, diluted with water
and extracted
with a suitable organic solvent, such as xylene or methyl tert-butyl ether.
The organic phase
is concentrated and the crude 2-(3-propoxy-phenoxy)-ethanol is purified by
means of
distillation.
In step 2, the 2-(3-propoxy-phenoxy)-ethanol formed in Step 1 above, is
further reacted
~o with a suitable reagent to produce a compound of formula 2,
o i I o~x
(2)
wherein X is a bromine, chlorine, iodine or a sulphonate ester group. Examples
of
~s sulphonate esters include, but are not limited to, alkane- and
arylsulphonate ester, e.g.
methanesulphonate, ethanesulphonate, p-toluenesulphonate, p-
bromophenylsulphonate.
Preferred compounds of formula 2 are sulphonate esters. Examples of reagents
capable of
producing preferred compounds of formula 2 include, but are not limited to,
methanesulphonyl chloride, ethanesulphonyl chloride, p-toluenesulphonyl
chloride and p-
zo bromosulphonyl chloride.
In Step 3, the compound of formula 2 in an organic solvent, such as methyl
tert-butyl ether
or toluene, is further reacted with isopropylamine in the presence of water.
The reaction is
performed at elevated temperature, preferably 60-11 (1"'C, for a prolonged
period of time
2~s and under increased pressure, preferably 1-10 atmospheres. Isopropylamine
should be
added at an excess, such as 2 to 6 equivalents, preferably 3-4 equivalents.
Optionally an
additional and non-nucleophilic base, such as potassium or sodium carbonate,
can be added
to the reaction mixture. The amount of water present in the reaction mixture
is not crucial
CA 02314988 2000-06-15
WO 99/32430 - PCT/SE98/02315
6
and can optionally be omitted. The reaction mixture is thereafter cooled and
aqueous acid
is added under vigorous stirring until the pH of the aqueous phase reaches a
constant value
of 3-5, preferably 3-3.5. The aqueous phase is separated, washed with methyl
tent-butyl
ether or toluene and thereafter used without any further purification in the
subsequent step.
In Step 4, the acidic aqueous solution of isopropyl-[2-(3-propoxy-phenoxy}-
ethyl]-amine
prepared in Step 3 above, is reacted with formaldehyde in the presence of
palladium on
charcoal. The reaction mixture is hydrogenated at atmospheric pressure or
above, such as
1-6 bars, for several hours. The amount of formaldehyde is not crucial, but
can be between
io 1-10 equivalents, by weight. The amount of palladium on charcoal used is
0.01 to 0.5
molar equivalents, preferably 0.05-0.2. The reaction mixture is thereafter
treated with
aqueous base, such as sodium hydroxide, to pH ~ 12 and extracted with methyl
tent-butyl
ether. The organic phase is separated and distillation gives pure isopropyl-
methyl-[2-(3-n-
propoxyphenoxy~thyljamine.
a
Surprisingly, we have been able to crystallize isopropyl-methyl-[2-(3-n-
propoxyphenoxy
ethyl]amine from the reaction mixture in step 4, by converting it to the
corresponding
monophosphate salt. The monophosphate salt of isopropyl-methyl-[2-(3-n-propoxy-
phenoxy)ethyl]amine is a crystalline and stable salt of isopropyl-methyl-[2-(3-
n-
2o propoxyphenoxy)ethyl]amine and therefore has advantageous properties. The
introduction
of a crystalline intermediate in the process for the preparation of isopropyl-
methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine is advantageous. It introduces a simple and
convenient
optional and additional purification step in a reaction sequence where all
intermediates are
syrups. Thereby, the time and energy consuming distillation used in processes
according to
2s prior art is avoided. The crystallization of the monophosphate salt of
isopropyl-methyl-[2-
(3-n-propoxyphenoxy)ethyl]amine results in an intermediate of a high purity
that can be
further converted to the corresponding isopropyl-methyl-[2-(3-n-propoxy
phenoxy)ethyl]amine by a simple alkalization step.
CA 02314988 2000-06-15
WO 99132430 - PCT/SE98/02315
7
In the optional purification step, the content of crude isopropyl-methyl-[2-(3-
n-propox~
phenoxy)ethyl]amine in ethyl acetate is first assayed and adjusted to 6-10 ml
ethyl acetate
per gram of crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine,
prepared instep
4 above. The content of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine in
ethyl
s acetate is preferably 7-9 ml ethyl acetate per gram of isopropyl-methyl-[2-
(3-n-propox~
phenoxy)ethyl]amine. To the assayed solution of isopropyl-methyl-[2-(3-n-
propoxyphenoxy)ethyi]amine, methanol and a solution of phosphoric acid in
methanol are
added. The amount of phosphoric acid should be around 0.9 to 1.0 molar
equivalents,
preferably 0.95 equivalents. The total amount of methanol added to the assayed
solution
to should be adjusted to the amount of phosphoric acid used. The concentration
of phosphoric
acid in the resulting solution of isopropyl-methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine in a
mixture of methanol and ethyl acetate should be around 5-15%, by volume,
preferably 9-
11 %, by volume. The precipitated salt is collected, for example by filtration
or
centrifugation, and thereafter washed with ethyl acetate.
Is
The monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine,
prepared above, is thereafter mixed with water and aqueous sodium hydroxide is
added to
pH ~ 11.5. Methyl tert-butyl ether, or other suitable solvent, is added and
the two phases are
separated. The organic phase is washed with water and concentrated yielding
pure
~o isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine.
The final distillation of crude isopropyl-methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine,
prepared by step 4 above, may be replaced by the optional purification
step,i.e. the
preparation of the monophosphate salt of isopropyl-methyl-[2-(3-n-
~s propoxyphenoxy)ethyl]amine. Under those circumstances the alkaline aqueous
phase
containing the crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine will
preferably be extracted with ethyl acetate instead of methyl tert-butyl ether.
The prepared
monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine can
thereafter be converted to the corresponding isopropyl-methyl-[2-(3-n-propox~
CA 02314988 2000-06-15
WO 99/32430 _ PCT/SE98/02315
8
phenoxy)ethyi]amine by a simple alkalization step. The mode of procedure can
easily be
made by a technician.
The present invention is described in more detail in the following non-
limiting examples.
s Roman numerals are referring to Scheme 1 and 2.
Examples
Example 1
~0 2-(3-Propoxy-phenoxy)-ethanol (1)
To 3-propoxyphenol ( I7.9 kg, I 17.4 mol) was added ethylene carbonate (20.7
kg, 234.8
mol), K2C03 (17.9 kg, 126.7 mol), tetrabutylammonium bromide (3.8 kg, 11.5
mol) and 1-
methyl-2-pyrrolidinone (56.5 L). The mixture is heated to ca 90~C for about 10
hours, then
cooled to 45°C where water ( 132 L) followed by methyl tent-butyl ether
(82 L) are added.
is The phases are separated and the organic phase is washed with 0.5 M HCl
(aq) followed by
0.5 M NaHC03 (aq). The organic phase is concentrated under reduced pressure
and the
crude 1 is purified by means of distillation, 150°C/0.95 mbar, yielding
I (I7.9 kg) as an oil
with a chromatographic purity over 97 %'o.
MS (EI): 196 (34), 153 (I3), 152 (7), 135 (4), 111 (67), 110 (100).'H NMR (200
MHz): 8
20 7.15 (t, 1 H), 6.5 (m, 3 H), 4.0 (m, 2 H), 3.9 (m, 4 H), 2.5 (s, 1 H), 1.79
(m, 2 H), 1.0 (t, 3
H). I3C NMR (50 MHz): 8 160.4, 159.8, 129.9, 107.2, 106.7, 101.6, 69.5, 69.2,
61.4, 22.6,
10.5.
Methanesulphonic acid 3-propoxy-phenoxyethyl ester (2)
I (17.9 kg, 91.0 mol) dissolved in methyl tent-butyl ether (83 L) and
triethylalriine (15.2 L,
as 108.1 mol) is allowed to react with MsCI (7.7 L, 99.12 mol). The resulting
slurry is
CA 02314988 2000-06-15
- WO 99/32430 - PCTISE98/02315
9
allowed to stand at ambient temperature for about 2 hours, water is added, the
phases are
separated and the organic phase is used as is in the subsequent step.
MS (EI): 274 (55), 232 (7), 195 ( 1 ), 153 (6), 135 ( 16), 123 ( 100), 110
(66), 79 (64).
s Isopropyl-[2-(3-propoxy-phenoxy)-ethyl]-amine (3)
To the solution of 2 are added K2C03 ( 14.0 kg, 98.1 mol), isopropylamine
(36.2 L, 455.9
mol) and water (3I L). The mixture is heated to 90°C for 16 hours with
the reactor sealed
resulting in a pressure of about 2 bar. The reaction mixture is cooled to
ambient
temperature, the aqueous phase is discarded and the organic phase is washed
with water.
~o To the organic phase is then added 0.5 M H2S04 (aq) to pH--3.5 and the
phases are
separated. The aqueous phase is washed with methyl tert-butyl ether and used
as is in the
subsequent step.
MS (EI): 237 (7), 222 (34), 194 ( 1), 135 (7), 85 (80), 72 (100). ~H NMR (200
MHz): 8 7.I
(m, 1H),6.5(m,3H),4.1 (t,2H),3.9(t,2H),3.0(t,2H),2.9(m,2H), 1.9(m,2H), 1.6
is (m, 1 H), 1.0 (d + t, 9 H). 13C NMR (50 MHz): 8 160.4, 160.1, 129.8, 107.0,
106.6, 101.5,
69.5, 67.6, 48.5, 46.5, 23.0, 22.6, 10.5.
CA 02314988 2000-06-15
WO 99132430 - PCT/SE98/02315
Isopropyl-methyl-[2-(3-propoxy-phenoxy)-ethyl]-amine (4)
To the acidic aqueous solution of 3 are added wet 10 % palladium on charcoal
(5.2 kg, 41.1
% Pd/C} and 37%a formaldehyde (20.3 L, 270.2 mol). The mixture is hydrogenated
at 3 bar
for about 4 hours. The reaction mixture is treated with conc. NaOH to pH-12,
The solids
are filtered off and the resulting two phase system is extracted with EtOAc.
The phases are
separated and the organic phase is washed with water and thereafter
concentrated. The
residue is distilled at 128-130°C/0.3 mbar to yield pure isopropyl-
methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine {18.1 kg, 72.1 mol).
io
Optional purification of crude isopropyl-methyl-[2-(3-propoxy-phenoxy)-ethyl]-
amine.
To a solution of crude 4 ( 19.0 kg, 75.7 mol) in ethyl acetate (8 ml ethyl
acetate per gram 4)
~s is added MeOH (9.6 L) followed by H3P04 ( 4.85 L, 72.5 mol) dissolved in
MeOH ( 19.2 L)
over 3 hours at ambient temperature. The resulting slurry of the monophosphate
salt of
isopropyl-methyl-[2-(3-n-propoxyphenoxy~thyl]amine is then isolated by
filtration and the
solid material is washed with EtOAc. The wet product (41.8 kg, 67.6 mol, 89 %
yield) with
a chromatographic purity over 99 % is used as is in the subsequent step.
2o Mp:131-134°C.
The content of H3P04 is 27.8 % (w/w) which corresponds to a 1:1 molar ratio
between 5
and H3P04 (28.0 % w/w theoretical value).
The wet product {41.8 kg, 67.6 mol) is mixed with water purified (66 L) and
conc. NaOH
is added to pH-11.5 and the resulting two phase mixture is extracted with
methyl tert-butyl
2s ether. The phases are separated, the organic phase is washed with water
purified and then
concentrated under reduced pressure. The residual solvents are finally
stripped off using a
thin film evaporator, affording isopropyl-methyl-[2-(3-n-
propoxyphenoxy)ethyl]amine
( 14.28 kg, 56.67'mol) as an oil with a chromatographic purity over 99 %.
MS (EI): 251 ( 10}, 236 (9), 86 ( 100). 1H NMR (400 MHz): 8 7.1 (m, 1 H), 6.5
(m, 3H), 4.0
30 (t, 2 H), 3.9 (t, 2 H), 2.9 (m, 1 H), 2.8 (t, 2 H), 2.3 (s, 3 H), 1.8 (m, 2
H), 1.0 (d + t, 9 H).
CA 02314988 2000-06-15
. - WO 99132430 _ PCT/SE98/02315
11
i3C NMR (50 MHz): S 160.3, 160.1, 129.7, 106.9, 106.5, 101.4, 69.4, 66.8,
54.0, 51.7,
38.2, 22.5, 17.9, 10.5.
Found %: C, 71.5; H, 10.3; N, 5.7; O, 12.5. Calculated %: C, 71.67; H, 10.02;
N, 5.57; O,
12.73.
s
