The present invention relates to a process for synthesising (+) 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl] acetamide monohydrochloride
(±) 2-Amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl] acetamide mono hydrochloride known as midodrine hydrochloride has been known for its efficacy as a cardio vascular drug due to its long lasting blood pressure increasing effect.
Of the several reported prior art for the synthesis of Midodrine hydrochloride, German patent specification DE 2523735 describes the use of substituted acetophenone as the starting material which is converted into the azido intermediate and then to the title compound. German patent specification DE 2506110 uses the amino alcohol intermediate as the starting material and uses the same reaction sequence disclosed in German patent DE 2523735 with the reduction of the azido group to the amino group in the final step using sodium borohydride or lithium aluminum hydride with additives and catalysts.

In these prior art synthetic processes, the first stage intermediate is obtained from disubstituted acetophenones through bromination, azidation and reduction with hazardous reducing agents such as lithium aluminium hydride. Further, the hitherto known processes for the synthesis of midodrine hydrochloride do not result in good yields. Yet another drawback of the existing processes is that they are not reproducible or consistent on larger scales with respect to selectivity, yield and purity.
Disclosure of the invention:
The objective of this invention is to synthesise (±) 2-amino-N-[2-(2,5-dimethoxy phenyl)-2-hydroxyethyl]acetamide monohydrochloride (I) using cost effective reagents, under easy operating conditions, in good yields and high purity. The process according to this invention results in a consistent quality product in reproducible yields.
The reaction sequence of the process according to this invention is shown hereunder.



The aminomethanone intermediate of the formula III shown in the reaction scheme is prepared by reacting l-(2,5-dimethoxy phenyl>2-bromoethanone of the formula II with hexamethylenetetramine in tetrahydrofuran doped with water. This novel step of carrying out the reaction in a medium containing tetrahydrofuran and water enhances the speed of the reaction considerably while producing better yield. The volume of the solvent system is not critical but aids uniform agitation of the reactants. It is observed that the reaction is completed within 30 minutes whereas use of other solvent systems takes considerably longer periods of about 24 hours for complete complex formation. It has also been noticed that addition of sufficient water to the reaction mixture for effective stirring avoids or minimizes the production of polymeric byproducts. The product is digested with methanol and concentrated HC1 as shown in step (a) in the reaction scheme. The resulting intermediate compound of formula III is washed with acetone and is found to have 99% purity.
Intermediate compound of formula IV is prepared by acylating \-{2,5-dimethoxy phenyl>2-amino ethanone of formula III using chloroacetyl chloride and sodium acetate in the presence of acetone-water mixture. Use of acetone water mixture in carrying out the reaction is found to give better yield with easy work up process. This reaction is shown in step (b) in the reaction scheme.

Reaction scheme shown in step (c) is for the preparation of the intermediate compound of formula V from the compound of formula IV obtained in step (b) by nucleophilic azidation using sodium azide. This reaction is carried out in acetone as against the acetone water mixture used in prior art disclosures. It has been observed that presence of water leads to lower yields due to side reactions.
The compound of formula V prepared by step (c) is converted into (±) 2-amino-N-[2-(2,5-dimethoxy phenyl)-2-hydroxyethyl] acetamide mono hydrochloride of formula I by reducing the carbonyl group selectively with sodium borohydride followed by reduction of the azide group with stannous chloride. There reactions are shown in step (d) and (e) in the reaction scheme. Prior art disclosed herein before follows simultaneous reduction of both the keto and azide groups in tetrahydrofuran using lithium aluminum hydride or sodium borohydride with 5% Palladium impregnated on carbon in methanol. Prior art methods suffer from disadvantages like difficulty in product isolation, product selectivity, and reproducibility on yields. The product conversion is very low with low purity. It has been found mat by selectively reducing the compound of formula V under mild reaction conditions, using stannous chloride which has so far not been adopted and yet readily available and relatively cheap, the title compound can be isolated directly with good yield. Improved yields are noticed when hydrochloric acid and acetone are added to the reaction mixture.

This invention, therefore, relates to a process for synthesising (±)2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl] acetamide mono hydrochloride which comprises the steps of:
(a) reacting l-(2,5-dimethoxy phenyl)-2-bromo ethanone with hexamine in tetrahydrofuran-water solvent system to produce l-(2',5'-dimethoxyphenyl)-2-aminoethanone;
(b) acylating said l-(2',5'-dimethoxyphenyl)-2-aminoethanone with haloacetylchloride and sodium acetate in acetone-water solvent medium to produce 2-chloro-N-(P-oxo-2,5-dimethoxyphenyl) acetamide;
(c) subjecting said acetamide obtained in step (b) to nucleophilic azidation with sodium azide in acetone medium to obtain 2-Azido-N-((3-oxo-2,5,dimethoxy phenethyl) acetamide;
(d) subjecting said 2-Azido-N-(P-oxo-2,5,dimethoxy phenethyl) acetamide to selective reduction of the carbonyl group by treating with sodium borohydride and;
(e) subsequently reducing the azide group with stannous chloride to obtain (±) 2-amino-N-[2-(2,5-dimethoxy phenyl)-2-hydroxyethy] acetamide which is converted into the corresponding monohydrochloride by treating with concentrated hydrochloric acid and recovered from the reaction mixture in a known manner.

Best method of carrying out the invention:
The following example describes the invention by way of illustration and is not included to limit the scope of the invention in any manner.
Step (a): Preparation of l-(2',5'-dimethoxvphenyl)ethanone amine
hydrochloride.
Quarternization:
In a four-neck round bottomed flask 500 gm of (1.93 mole) of 1-(2,5,-dimethoxyphenyl>-2-bromoethanone is added. 7500 ml of tetrahydrofuran is added to dissolve the solid. The agitator is switched on and solid gets dissolved immediately. 75 ml of water added into the flask under agitation. 270 gm of hexamine (1.93 mole) is added through powdered funnel. Immediately after the addition of hexamine thick precipitation is observed. Agitation is continued for 2 hours at ambient temperature. The resulting white precipitate is filtered under vacuum and the cake is washed with THF.
Conversion to aminehydrochloride:
780 gms of solid obtained according to example (a) is taken into a round bottomed flask. 15600 ml of methanol is added and agitation is initiated.

OoU ml of concentrated HC1 is added into the flask and agitation is continued. The mass is heated to reflux and maintained for lhr. The mass is evaporated to dry and cooled down. Acetone is added to this and stirred for 10 minutes, filtered, washed with acetone and dried under vacuum. The yield was 85%.
Step (b): Preparation of 2-CMoro-N-(p-oxo-2,5-Dimethoxy phenethyl)-acetamide.
In a four neck round bottomed flask, 1500 ml of acetone is charged. 240 gm of l-(2',5'-dimethoxyphenyl)ethanone amine hydrochloride prepared according to step (a) is added under stirring. 500 ml of water is charged into the flask under stirring. The reaction mass is cooled down to 0°C under stirring. 330 gm of sodium acetate is added till a pH of 5 is obtained. 77 gm of chloro acetyl chloride is added slowly over a period of 30 minutes while maintaining the temperature of 0°C. After addition is completed the reaction mass is stirred for 30 minutes. Agitation is stopped and the bottom aqueous layer is separated. The organic layer is concentrated and water is added. The precipitated material is filtered and dried. The solid is crystallized from methanol.
I

The following physical properties are measured. Melting point: 140-142°C.

'H-NMRCCDCb) : 6(ppm) 3.9(3Rs,H-l),
3.7(3H,s,H-4), 4.1(2H,s,H-8), 4.7(2H,d,H-6), 6.9(1 H,d,H-2), 7.1(lH,dd,H-3), 7.5(lH,d,H-5), 7.7(lH,s,H-7).
Step (c): Preparation of 2-Azido-N-{p-Oxo-2,5-dimethoxy phenehyl)-acetamide.
In a four neck round bottomed flask, 45 gm (0.165mole) of 2-Chloro-N-(p-oxo-2,5-Dimethoxy phenethyl)-acetamide prepared according to step (b), 27g (0.415 mole) sodium azide and 8.3 g (0.049 mole) potassium iodide

and 900 ml of acetone is charged. The solution is refluxed at 60°C for 5 hours. After completion of the reaction the reaction mass cooled and filtered to remove inorganics. Acetone is distilled off under atmospheric pressure. Water is added and the resulting yellow lumps are filtered. (Yield:91%). The solid is recrystallized from methanol. The following physical properties are measured. Melting point: 104-106°C.

!H-NMR(CDCl3) 8(ppm) 3.9(3H,s,H-l),
3.7(3H,s,H-4), 4.0(2H,s,H-8), 4.7(2H,d,H-6), 6.9(1 H,d,H-2), 7.1(lH,m,H-3), 7.4