U.S. patent application number 10/040385 was filed with the patent office on 2002-09-12 for process for the preparation of midodrine.
This patent application is currently assigned to Chemagis Ltd.. Invention is credited to Brand, Michael, Chen, Ronit, Kaspi, Joseph, Yigal, Deby.
Application Number | 20020128511 10/040385 |
Document ID | / |
Family ID | 11075177 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020128511 |
Kind Code |
A1 |
Brand, Michael ; et
al. |
September 12, 2002 |
PROCESS FOR THE PREPARATION OF MIDODRINE
Abstract
The invention provides a process for the preparation of
2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide of the
formula 1 by hydrogenolysis of substituted
2-dibenzylamino-N-[2-(2',5'-di-
methoxyphenyl)-2-hydroxy-ethyl]acetamide having the formula (5),
wherein Ar and Ar' are aryl groups. 1
Inventors: |
Brand, Michael; (Raanana,
IL) ; Chen, Ronit; (Rehovot, IL) ; Yigal,
Deby; (Tzur Yigal, IL) ; Kaspi, Joseph;
(Givatayim, IL) |
Correspondence
Address: |
BANNER & WITCOFF
1001 G STREET N W
SUITE 1100
WASHINGTON
DC
20001
US
|
Assignee: |
Chemagis Ltd.
Bnei Brak
IL
|
Family ID: |
11075177 |
Appl. No.: |
10/040385 |
Filed: |
January 9, 2002 |
Current U.S.
Class: |
564/196 |
Current CPC
Class: |
C07C 237/08 20130101;
C07C 231/12 20130101; C07C 237/08 20130101; C07C 231/12
20130101 |
Class at
Publication: |
564/196 |
International
Class: |
C07C 231/12 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 2001 |
IL |
141,655 |
Claims
What is claimed is:
1. A process for the preparation of
2-amino-N-[2-(2,5-dimethoxyphenyl)-2-h- ydroxyethyl]acetamide of
the formula 1 by hydrogenolysis of substituted
2-dibenzylamino-N-[2-(2',5'-dimethoxyphenyl)-2-hydroxyethyl]acetamide
having the formula (5), wherein Ar and Ar' are aryl groups. 8
2. A process according to claim 1 in which the compound of formula
(5) is prepared by reacting
2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]a- cetamide of
formula (3) with a substituted dibenzylamine of the formula (6).
9wherein Ar and Ar' are optionally substituted phenyl groups.
3. A process according to claim 2 wherein the aryl ar and ar'
groups are indipendtly phenyl or substituted phenyl groups wherein
these substituents are chosen from C.sub.1-C.sub.4 alkyl groups,
C.sub.1-C.sub.4 alkoxy groups, C.sub.1-C.sub.4 dialkylamino groups
and halo groups.
4. A process according to claim 3 wherein both Ar and Ar' groups in
formula (6) are phenyl groups.
5. A process according to claim 1 wherein the hydrogenolysis
reaction is done by hydrogen over a palladium on carbon
catalyst.
6. A process according to claim 3 wherein the hydrogen pressure is
between 4-6 bars.
7. A process according to claims 3 and 4 wherein the reaction
temperature is between 40.degree.-70.degree. C.
8. A process according to claims 3, 4 and 5 wherein the reaction
medium is an alcohol of the formula ROH in which R is a
C.sub.1-C.sub.4 alkyl group.
9. A process according to claim 6 wherein the reaction medium is
ethanol.
10.
2-dibenzylamino-N-[2-(2',5'-dimethoxyphenyl)-2-hydroxyethyl]acetamide
having the formula (7). 10
Description
[0001] The present invention is related to a novel process for the
preparation of
2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamid- e
hydrochloride, also known as Midodrine hydrochloride, having the
following formula (1). 2
BACKGROUND OF THE INVENTION
[0002] Midodrine is classified as an antihypotensive drug. It was
first described and claimed in the U.S. Pat. No. 3,340,298. The
drug is dispensed in tablet form as the hydrochloride salt having
the structure (1).
[0003] The key intermediate required for preparing Midodrine is
1-(2,5-dimethoxyphenyl)-2-aminoethanol hydrochloride having the
structure (2). 3
[0004] The synthesis of Midodrine HCl consists of reacting the key
intermediate (2) with chloroacetyl chloride to afford
2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (3).
The reaction of (3) with sodium azide will provide
2-azido-N-[2-(2,5-dimethox- yphenyl)-2-hydroxyethyl]acetamide (4)
which is subsequently subjected to hydrogenation to afford
Midodrine base (6).
[0005] Acidification with aqueous HCl will provide Midodrine HCl
(1). The above sequence of reactions are outlined in the following
scheme (see for example Austrian patent AT 336584). 4
[0006] A serious drawback in the above synthesis of Midodrine HCl
involves the use of the dangerously explosive sodium azide. In
addition, the above synthesis will involve the formation of the
organic azide (4), which is also a potentially explosive material.
Both sodium azide and the azide (4) are also toxic materials.
[0007] The development of a process for Midodrine HCl, which avoids
the use of the highly toxic and explosive sodium azide, will be of
great benefit.
SUMMARY OF THE INVENTION
[0008] According to the present invention, a process is now
available for the preparation of Midodrine hydrochloride (1) via a
safe process. In addition, all of the intermediates involved in the
preparation of (1) are safe to handle. In the present invention,
the toxic and potentially explosive sodium azide is replaced by a
safe to handle bis (substituted) diaryl amine, preferably
dibenzylamine. The new synthesis of Midodrine HCl consists of
reacting 1-(2,5-dimethoxy-phenyl)-2-aminoethanol hydrochloride (2)
with chloroacetyl chloride in a mixture of methylene chloride and
aqueous potassium hydroxide solution at 5.degree.-10.degree. C. to
produce
2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetami- de
(3).
[0009] The chloro acetamide derivative (3) is not isolated but
reacted in situ, after removal of the methylene chloride, with a
bis (substituted) diarylamine having formula (6) in refluxing
toluene for a period of about 10 hours. Ar and Ar' groups in
formula (6) are independently phenyl or substituted phenyl groups.
The substituents can be chosen from C.sub.1-C.sub.4 alkyl groups,
C.sub.1-C.sub.4 alkoxy groups, C.sub.1-C.sub.4 dialkylamino groups
and halo groups. The preferred amine of formula (6) is dibenzyl
amine of formula (8) wherein both Ar and Ar' groups are phenyl
groups The product, 2-(substituted)-dibenzylamino-N-[2--
(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (5) is isolated by
filtration. In the next step, the intermediate (5) is
hydrogenolyzed to give Midodrine free base (9). The hydrogenolysis
is performed at 40.degree.-70.degree. C., preferably 50.degree. C.,
and 4-6 bar hydrogen pressure using 5% Pd/C as catalyst. The
reaction is performed in an alcoholic medium, preferably ethanol.
After removal of the alcohol, the Midodrine base (9) is isolated by
filtration.
[0010] In the final step, the Midodrine base (9) is dissolved in
ethanol. The addition of a solution of HCl gas in isopropanol
causes the hydrochloride salt of Midodrine to separate from
solution. A filtration will afford Midodrine HCl (1) in a highly
pure form.
[0011] It should be pointed out that all of the reagents as well as
the intermediates involved in the process can be safely handled and
provide no safety risks. The above sequence of reactions is
outlined in the following scheme. 5
[0012] While the invention will now be described in connection with
certain preferred embodiments in the following examples so that
aspects thereof may be more fully understood and appreciated, it is
not intended to limit the invention to these particular
embodiments. On the contrary, it is intended to cover all
alternatives, modifications and equivalents as may be included
within the scope of the invention as defined by the appended
claims. Thus, the following examples which include preferred
embodiments will serve to illustrate the practice of this
invention, it being understood that the particulars shown are by
way of example and for purposes of illustrative discussion of
preferred embodiments of the present invention only and are
presented in the cause of providing what is believed to be the most
useful and readily understood description of formulation procedures
as well as of the principles and conceptual aspects of the
invention.
EXAMPLES
Example 1
Preparation of
2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamid- e
[0013] The reaction vessel is charged with 15.5 g
1-(2,5-dimethoxyphenyl)-- 2-amino-ethanol hydrochloride, 115 ml
methylene chloride and 100 ml water. The mixture is stirred at
25.degree.-30.degree. C. to afford a clear two-phase mixture. The
mixture is cooled to 5.degree.-10.degree. C. and a solution of 18.7
g of 50% potassium hydroxide and 18.5 ml water is added in portions
at 5.degree.-10.degree. C.
[0014] The mixture is stirred at 5.degree.-10.degree. C. for 15
min. 8.0 ml of chloroacetyl chloride is added in portions at
5.degree.-10.degree. C. causing an exothermic reaction to occur. On
completion of the addition, the pH should be adjusted to 3-6. The
mixture is allowed to warm to 25.degree.-30.degree. C. and the pH
is adjusted again to 3-6. After stirring for one hour at
25.degree.-30.degree. C., the pH is adjusted to 6-7 with 5% aqueous
potassium hydroxide solution. The stirring is stopped and the
layers are separated.
[0015] The upper aqueous layer is washed with 25 ml of methylene
chloride. The organic layers are combined and dried over magnesium
sulfate. The solution of
2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide in
methylene chloride is used as is in the next step.
Example 2
Preparation of
2-dibenzylamino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]a-
cetamide
[0016] The reaction vessel is charged with the methylene chloride
solution of
2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide
prepared in example 1. The majority of the methylene chloride is
distilled off at atmospheric pressure. On completion of the
distillation 155 ml toluene are added. The mixture is stirred to
obtain a solution. 45 to 50 ml of the toluene is distilled to
remove the remainder of methylene chloride. The mixture is cooled
to 85.degree.-90.degree. C. and 28.4 g dibenzylamine is added in
portions at 85.degree.-90.degree. C. On completion of the addition,
the mixture is heated to reflux for a period of 10 hours.
[0017] On completion of reaction, the resulting suspension is
cooled to 45.degree.-50.degree. C. 110 ml water are added followed
by 7.5 g of 50% potassium hydroxide. The mixture is stirred at
25.degree.-30.degree. C. for a period of 2-3 hours during which
time the product crystallizes from solution. After cooling to
5.degree.-10.degree. C., the product is filtered to afford 21.7 g
of 2-dibenzylamino-N-[2-(2,5-dimethoxyphenyl)-2-
-hydroxyethyl]acetamide. This represents a 75% yield based on the
starting material from example 1. The product is characterized as
follows:
[0018] m.p.: 110.0-111.1.degree. C.
[0019] MS: 434 (M.sup.+)
[0020] .sup.1H-NMR (DMSO-d.sub.6): 7.65 ppm, triplet, J=6 Hz,
CH.sub.2--NH, 1H; 7.35-7.26 ppm, multiplet, benzyl aromatic
protons, 10H; 7.06-6.81 ppm, multiplet, dimethoxy aromatic protons,
3H; 5.60 ppm, doublet, J=5 Hz, CH--OH, 1H; 4.95 ppm, multiplet,
CH--OH, 1H; 3.71 and 3.65 ppm, two singlets, two OCH.sub.3, 6H;
3.54 ppm, broad singlet, two CH.sub.2-Ph, 4H; 3.36 ppm, singlet,
H.sub.2O; 3.45 and 3.15 ppm, two multiplets, CH.sub.2--NH, 2H; 2.93
ppm, broad singlet, CH.sub.2--N, 2H. .sup.13C-NMR (DMSO-d.sub.6):
169.62 ppm, C.sub.11; 153.19+149.82 ppm, C.sub.1+C.sub.4; 138.21
ppm, C.sub.15/C.sub.21; 132.26 ppm, C.sub.6; 128.78 ppm,
C.sub.16/C.sub.20/C.sub.22/C.sub.26; 128.31 ppm,
C.sub.17/C.sub.19/C.sub.23/C.sub.25; 127.14 ppm, C.sub.18/C.sub.24;
112.79+112.25+111.59 ppm, C.sub.2+C.sub.3+C.sub.5; 65.49 ppm,
C.sub.9; 57.72 ppm, C.sub.13/C.sub.14; 56.45 ppm, C.sub.12;
55.80+55.18 ppm, C.sub.7+C.sub.8; 44.38 ppm, C.sub.10. 6
Example 3
Preparation of
2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide
(Midodrine base)
[0021] An autoclave is charged with 15.0 g of
2-dibenzylamino-N-[2-(2,5-di-
methoxyphenyl)-2-hydroxyethyl]acetamide, 200 ml ethanol and 1.5 g
of 5% Pd/C catalyst. The system is flushed three times with
nitrogen followed by hydrogen. The pressure of hydrogen is adjusted
to 4-6 bar. The temperature is adjusted to 45.degree.-50.degree. C.
The mixture is stirred and heated at 45.degree.-50.degree. C. for
24 hours.
[0022] On reaction completion, the mixture is cooled to
25.degree.-30.degree. C. and filtered through a Celite pad to
separate the catalyst. The clear f/Uiltrate is transferred to a
clean reaction vessel. About 1/2 of the ethanol is distilled out at
atmospheric pressure. On cooling and seeding, Midodrine base will
crystallize from solution. After cooling to 5.degree.-10.degree.
C., the product is filtered to afford 6.3 g (71% yield) of white
Midodrine base. The product is characterized as follows:
[0023] m.p.: 105.8.degree.-106.8.degree. C.
[0024] MS: 254 (M.sup.+)
[0025] .sup.1H-NMR (DMSO-d.sub.6): 7.88 ppm, triplet, J=6 HZ,
CH.sub.2--NH, 1H; 7.02-6.76 ppm, multiplet, aromatic protons, 3H;
5.42 ppm: broad singlet, CH--OH, 1H; 4.90 ppm, multiplet, CH--OH,
1H; 3.73+3.70 ppm, two singlets, two OCH.sub.3, 6H; 3.45+3.01 ppm,
two multiplets, CH.sub.2--NH, 2H; 3.06 ppm, broad singlet,
CH.sub.2--NH.sub.2, 2H. .sup.13C-NMR (DMSO-d.sub.6): 172.75 ppm,
C.sub.11; 153.11+149.65 ppm, C.sub.1+C.sub.4; 132.45 ppm, C.sub.6;
112.53+112.17+111.48 ppm, C.sub.2+C.sub.3+C.sub.5; 65.64 ppm,
C.sub.9; 55.74+55.18 ppm, C.sub.7+C.sub.8; 44.82+44.54 ppm,
C.sub.10+C.sub.12. 7
Example 4
Conversion of Midodrine Base to Midodrine hydrochloride
[0026] The reaction vessel is charged with 5.0 g Midodrine base and
60 ml ethanol. The mixture is heated to reflux to obtain a clear
solution. To the hot mixture is added 6.3 ml of a 22% solution of
hydrochloric acid in isopropanol in portions. During the addition,
the Midodrine HCl will crystallize from solution. After cooling to
5.degree.-10.degree. C., the product is filtered to afford 4.8 g
(96% yield) of Midodrine HCl (m.p.: 200.8.degree.-201.8.degree.
C.).
[0027] It will be evident to those skilled in the art that the
invention is not limited to the details of the foregoing
illustrative examples and that the present invention may be
embodied in other specific forms without departing from the
essential attributes thereof, and it is therefore desired that the
present embodiments and examples be considered in all respects as
illustrative and not restrictive, reference being made to the
appended claims, rather than to the foregoing description, and all
changes which come within the meaning and range of equivalency of
the claims are therefore intended to be embraced therein.
* * * * *