FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of midodrine using a novel intermediate, tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate of formula (VI). The process comprises reaction of 2-amino-l-(2,5-dimethoxyphenyl)-ethanone hydrochloride of formula (Va) with N-BOC-glycine in presence of 1,1'carbonyldiimidazole (CDI) to give compound (VI), which, when subjected to reduction with sodium borohydride, followed by treatment with hydrochloric acid affords midodrine hydrochloride (la) conforming to regulatory specifications.
BACKGROUND OF THE INVENTION
Midodrine of formula (I), chemically known as 1-(2',5'-dimethoxyphenyl)-2-glycinamidoethanol or (RS)-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]glycinamide, is an antihypotensive agent, which is administered as its hydrochloride salt (la). Midodrine was initially approved in the United States by USFDA in 1996 (proamatine by Shire LLC) for the treatment of orthostatic hypotension and dysautonomia and is presently marketed by Up Sher Smith under the brand name orvaten.
The process for preparation of midodrine (I) was first disclosed in US 3,340,298 wherein the key intermediate 2-amino-l-(2'35,-dimethoxyphenyl)-ethanol was reacted with protected amino acids or their derivatives in presence of N,N'-dicyclohexylcarbodiimide (DCC). The amide intermediate so obtained was subjected to hydrogenation in acetic acid to get the desired compound, midodrine.
Use of DCC in the above reaction sequence gives rise to a toxic by-product, N,N'-dicyclohexylurea (DCU). Complete separation of DCU from the reaction mixture is a difficult task due to its insolubility in most of the organic solvents and the traces of this side product

which remain after physical separation cause serious contamination problems to further reactions, making this synthetic route unviable on commercial scale.
US 6,201,153 discloses a synthesis method wherein the key aminoethanol intermediate, 2-amino-l-(2,5-dimethoxy)phenyl ethanol is synthesized by reduction of the keto azide compound, l-(2',5'dimethoxyphenyl)-2-azidoethanone. The aminoethanol intermediate is then reacted with an anhydride prepared from reaction of N-Boc-glycine and DCC to obtain Boc-protected midodrine, which is treated with hydrochloric acid in polar aprotic solvent to get midodrine hydrochloride.
Although this process attempts to avoid interference of problematic side product N,N'-dicyclohexylurea (DCU) by using the anhydride, factors such as a) use of toxic and dangerously explosive sodium azide, b) synthesis of potentially hazardous organic azides, c) additional synthetic steps for anhydride preparation, and d) low-temperature filtration of DCU from the anhydride reaction mixture adversely affect the overall yield rendering the process uneconomical.
US 6,444,851 discloses a process for the synthesis of midodrine comprising the treatment of ethanolamine intermediate with chloroacetyl chloride to give the chloroacetamide derivative, which is further treated with substituted diarylamines like dibenzyl amine, followed by hydrogenation of the diaryl-protected intermediate to yield midodrine.
The above synthesis sequence, although free from hazardous hydrazide intermediate, involves toxic reagents like chloroacetyl chloride and amination of chloro compound using substituted diaryl amines, which are later removed by hydrogenation. Use of toxic reagents, requirement of equipment for pressure reactions, lengthy hydrogenation reactions make this reaction sequence difficult to operate on industrial scale.
WO2004/080946 discloses a synthetic route (Scheme-1) wherein the aminoethanol intermediate, 2-amino-1-(2',5' -dimethoxyphenyl)-ethanol, obtained from borohydride reduction of the corresponding ketone, 2-amino-l(2,5-dimethoxyphenyl)-ethanone, is reacted

with amino-protected glycine derivative in presence of l,rcarbonyldiimidazole (CDI), followed by deprotection of the obtained intermediate to yield midodrine.
Scheme 1: Method embodied in WO2004/080946 for the preparation of midodrine hydrochloride
While the aforementioned sequence avoided toxic and hazardous reagents and did not involve the problems associated with the use of DCC, the reaction which yields the key intermediate, 2-amino-l-(2',5'-dimethoxyphenyl)-ethanol takes place with a very modest yield of 30-36%.
It was experimentally observed that the poor yield for this otherwise simple borohydride reduction reaction could be attributed to the high solubility of resulting amino-alcohol intermediate in water. This extreme hydrophilicity of the key intermediate results in incomplete extractions from aqueous reaction medium. This not only results in yield losses but also creates serious problems of high organic load in the effluent, removal of which is essential due to environmental concerns and causes steep increase in the process cost.

It is pertinent to note that almost all synthetic routes for midodrine disclosed in prior art involve the intermediate 2-amino-1-(2',5'-dimethoxyphenyl)-ethanol and hence the aforementioned hydrophilicity problem is prevalent in all these prior art processes.
Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of midodrine hydrochloride (la) which avoids hydrazide type intermediates, hazardous reagents such as chloroacetyl chloride, DCC and employs a simple, cost-effective and environment friendly synthetic approach with minimum interference of side products and associated impurities.
The present inventors have developed a novel process for synthesis of midodrine hydrochloride (la) wherein the use of highly hydrophilic intermediate 2-amino-l-(2\5'-dimethoxyphenyl)-ethanol is avoided. The synthesis is accomplished by treating 2-amino-1(2,5-dimethoxyphenyl)-ethanone hydrochloride of formula (Va) with lj'carbonyldiimidazole (CDI) and N-BOC-glycine, also known as N-(tert-butoxycarbonyl)glycine to give tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate of formula (VI) in 85% yield. Compound (VI) on reduction and hydrochloric acid treatment gave midodrine hydrochloride in more than 65% overall yield. Thus, by avoiding the water soluble, highly hydrophilic intermediate, the yield for its corresponding steps improved significantly, which, in turn gave more than 20%) higher overall yield for midodrine as compared to prior art.
OBJECT OF THE INVENTION
An objective of the present invention is to provide midodrine hydrochloride of formula (la) having desired purity by a convenient and industrially viable process which does not involve hazardous hydrazides or extremely hydrophilic, difficult-to isolate intermediates.
Another object of the present invention is to provide an efficient, cost-effective and environment-friendly process for preparation of midodrine hydrochloride (la) which includes novel intermediate, tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate, which affords midodrine in substantially higher yield as compared to prior art processes.

SUMMARY OF THE INVENTION
The present invention relates to a novel method for synthesis of l-(2'?5'-dimethoxyphenyl)-2-glycinamidoethanol hydrochloride of formula (la) having desired purity.
An aspect of the invention relates to a process for preparation of midodrine hydrochloride (la) comprising reaction of 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride of formula (Va) with N-(tert-butoxycarbonyl)glycine in presence of 1,1'carbonyldiimidazole (CDI) and solvent ethyl acetate to give tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate of formula (VI), which on reduction with sodium borohydride gave tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-carbamoyl} methyl) carbamate of formula (VII). Further treatment of compound (VII) with hydrochloric acid afforded midodrine hydrochloride (la) having purity conforming to regulatory specifications.
The objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
As evident from the structural features of midodrine, the ethanolamine derivative, 2-amino-l-(2,,5'-dimethoxyphenyl)-ethanol is a key intermediate in the synthesis of midodrine and most of the synthetic strategies for midodrine as disclosed in the prior art have resorted to this intermediate.
However, while carrying out extensive experimentation for development of a simple, economically viable process for midodrine, the present inventors observed that the extreme hydrophilic nature of the ethanolamine intermediate posed serious problems for the synthetic processes, irrespective of the synthetic route followed to obtain it. The intermediate could never be completely extracted from the aqueous reaction mass, which severely affected the output for the specific synthetic step and caused a drastic negative impact on the overall yield.

In addition, since the intermediate remained in the aqueous layer in considerable quantities, it increased the organic load on the effluent, which was a serious environmental concern. This necessitated solvent extractions, elaborate treatment procedures and various unit operations for the effluent, which substantially added to the total operation time and overall project cost.
While pursuing the development of an industrially viable and economical process for synthesis of midodrine, the present inventors have surprisingly found that the drawbacks mentioned in prior art could be avoided by use of a novel ketone-intermediate, tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate of formula (VI) in the synthetic strategy. The intermediate (VI) was prepared by reaction of 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride (compound V) with lj'carbonyldiimidazole (CDI) and N-BOC-glycine. The compound (VI) thus obtained was subjected to reduction with sodium borohydride, followed by treatment of the resulting compound (VII) with hydrochloric acid to give midodrine hydrochloride (la) conforming to regulatory specifications.
The present route avoids involvement of extremely hydrophilic ethanolamine derivative, 2-amino-1 -(2',5' -dimethoxyphenyl)-ethanol in the synthetic strategy. Instead, a ketone derivative (compound V) is reacted with CDI and N-BOC-glycine to give intermediate (VI), which does not exhibit hydrophilicity, thus enabling complete extraction and work up procedures. This causes an unexpected yield enhancement, ease of operation, reduced organic load on effluent, ultimately resulting in substantial yield improvement for midodrine.
Thus, by avoiding the most common ethanol amine intermediate, a four-fold overall yield enhancement with respect to midodrine hydrochloride is observed when compared to prior art methods involving the said intermediate.

Scheme 2: Method embodied in the present invention for the preparation of midodrine hydrochloride (la)
In an embodiment, 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride of formula (Va), was treated with 1,1'carbonyldiimidazole (CDI) and N-BOC-glycine in the temperature range of 10-30°C in an organic solvent to yield tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate of formula (VI).
The organic solvent was selected from the group comprising methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate and the like.
After completion of reaction as monitored by HPLC, the reaction mass was quenched with water, the organic layer was separated, concentrated and treated with methanol and water to isolate compound (VI).

The compound (VI) was further dissolved in methanol; optionally in presence of other solvent such as dichloromethane, and treated with sodium or potassium borohydride at 25-30 °C till completion of the reaction, as monitored by HPLC. After completion of the reaction, the reaction mass containing tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-carbamoyl} methyl) carbamate of formula (VII) was quenched with careful addition of water and extracted with ethyl acetate. The organic layer was separated and treated with hydrochloric acid to yield midodrine hydrochloride (la) of desired purity.
2-amino-1 (2,5-dimethoxyphenyl)-ethanone, Compound (V) was prepared from 1 -(2,5-dimethoxyphenyl)ethanone (II) following procedures known in the prior art. Compound (II) was treated with bromine in dichloromethane at 0-5°C to give 2-bromo-l-(2,5-dimethoxyphenyl)ethanone (III), which on further reaction with hexamethylene tetramine, followed by acid treatment of the resulting addition compound (IV) gave 2-amino-1(2,5-dimethoxyphenyl)-ethanone hydrochloride (Va).
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES
Example 1: Preparation of 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride (Va)
Hexamethylene tetramine (54. lg) was added to the stirred mixture of 2-bromo-l-(2,5-dimethoxyphenyl)ethanone; ( Compound (III), 100.2g), water (15 ml) and acetone (1300 ml) at 25-30°C. Stirring was continued till completion of the reaction as monitored by TLC. After completion of reaction, the reaction mixture was filtered, solid was separated and dried to give the hexamethylene tetramine salt of compound III (155.4g).
Concentrated hydrochloric acid (310 ml) was gradually added to the stirred mixture of hexamethylene tetramine salt of compound III (155.4g) and methanol (930 ml) at room temperature. The reaction mixture was heated to 60-65°C with continued stirring till completion of the reaction as monitored by TLC.

After completion of reaction, the reaction mixture was concentrated and acetone was added to the residue. The stirred mass was cooled and filtered to give 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride (Va). Yield: 117.1 g
Example 2: Preparation of tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate (VI)
N-BOC-glycine (83.2 g), was gradually added to the mixture of 1,1'carbonyldiimidazole (CDI) (77.0 g) and ethyl acetate (500 ml) in the temperature range of 10-30°C and the reaction mixture was stirred. 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride, (100.3 g, on assay basis) was gradually added to the mixture at 10-20°C and the reaction mass was stirred at the same temperature till completion of the reaction as monitored by HPLC. After completion of the reaction, the reaction mixture was quenched with water, the organic layer was separated and concentrated. Methanol and water were added to the concentrate , the mixture was stirred at room temperature and filtered to get tertiary-butyl-N-({[2-(2,5-dimethbxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate (VI). Yield: 121.7 g (80.1%)
Example 3: Preparation of midodrine hydrochloride (la)
Sodium borohydride (3.22 g) was gradually added to a solution of tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate (100.3 g) in methanol (1200 ml) at 25-30°C and reaction mixture was stirred till completion of the reaction. After completion, as monitored by HPLC, the reaction mixture was quenched by carefiil addition of water and extracted with ethyl acetate. The organic layer was separated and treated with hydrochloric acid (55 ml) at 25-30°C to give midodrine hydrochloride (la). Yield: 61.9 g (75%)

CLAIMS
We claim,
1. A process for the preparation of midodrine hydrochloride (la), comprising reaction of 2-amino-l(2,5-dimethoxyphenyl)-ethanone hydrochloride of formula (Va) with N-(tert-butoxycarbonyl)glycine in presence of lj'carbonyldiimidazole (CDI) in an organic solvent to give tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate of formula (VI), which, on reduction gave tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-carbamoyl} methyl) carbamate of formula (VII), which, after treatment with hydrochloric acid gave midodrine hydrochloride (la).
2. A process as claimed in claim 1, wherein the organic solvent is selected from a group comprising methyl acetate, ethyl acetate, n-propyl acetate and n-butyl acetate.
3. A process as claimed in claim 1, wherein the reaction to give compound (VI) is carried out in the temperature range of 10-30°C.
4. A process as claimed in claim 1, wherein compound (VI) is isolated by concentration of the organic layer containing compound (VI) and treatment with methanol and water.
5. A process as claimed in claim 1, wherein the reduction is carried out using sodium borohydride or potassium borohydride.
6. A process utilizing tertiary-butyl-N-({[2-(2,5-dimethoxyphenyl)-2-ketoethyl]-carbamoyl} methyl) carbamate (VI) for the preparation of midodrine hydrochloride of formula (la).