Intermediate for preparing midodrine

Details Intermediate for preparing midodrine Intermediate for preparing midodrine

2002-07-30

2003-08-26

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S163000

Reexamination Certificate

active

06610886

ABSTRACT:

The present invention is related to a novel process for the preparation of 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide hydrochloride, also known as Midodrine hydrochloride, having the following formula (1).
BACKGROUND OF THE INVENTION
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).
The key intermediate required for preparing Midodrine is 1-(2,5-dimethoxyphenyl)-2-aminoethanol hydrochloride having the structure (2).
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-dimethoxyphenyl)-2-hydroxyethyl]acetamide (4) which is subsequently subjected to hydrogenation to afford Midodrine base (6).
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).
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.
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
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°-10° C. to produce 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide (3).
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
1
-C
4
alkyl groups, C
1
-C
4
alkoxy groups, C
1
-C
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°-70° C., preferably 50° 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.
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.
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.
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.


REFERENCES:
patent: 3340298 (1967-09-01), Karl et al.
patent: 1003659 (1965-09-01), None
patent: 7-285921 (1995-10-01), None

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