FIELD OF THE INVENTION
The present invention provides a novel and an industrially advantageous process for the preparation of pure metaraminol or salts thereof. In particular, the present invention provides a novel and cost effective process for the preparation of enantiomerically pure metaraminol bitartrate.
BACKGROUND OF THE INVENTION
Metaraminol bitartrate of formula I, is a potent sympathomimetic amine used for the treatment of hypotension, and is chemically known as [R-(R*,S*)]-a-(l-aminoethyl)-3-hydroxybenzenemethanol [R-(R*,R*)]-2,3-dihydroxybutane dioate (1:1) (salt).
OH OH 0 Formula I
H0vvV H0YV^H
W NH2 0 OH
It is an adrenergic agonist that acts predominantly at alpha adrenergic receptors and also stimulates the release of nor-epinephrine. It has been used primarily as a vasoconstrictor in the treatment of hypotension and is being marketed under the trade name ARAMINE®.
The levo compounds of l-hydroxyphenyl-2 aminopropan-1-ol series including metaraminol [racemic] was first disclosed in US patent 1,951,302. The process to prepare levo compounds of l-hydroxyphenyl-2 aminopropan-1-ol has also been disclosed by catalytically reducing optically active l-meta-hydroxyphenyl-2-keto-propan-1-ol in the presence of ammonia or primary amines. In the exemplified process preparation of levo-l-metahydroxyphenyl-2 aminopropan-1-ol has been disclosed by the reaction of levo-meta-hydroxyphenylacetylcarbinol using alcoholic ammonia^enzylamine/methylamine followed by hydrogenation with palladium and hydrogen and the resulting compound which has difficulty in crystallization has been isolated as hydrochloride salt.
Similar processes to prepare levo 1-meta -hydroxyphenyl-2 aminopropan-1-ol by reducing optically active l-meta-hydroxyphenyl-2-keto-propan-l-ol, with minor

modifications [such as use of ammonia or primary amines or precious metal catalysts] have also been disclosed in United Kingdom patents, GB365335 and GB 396551. The above processes do not teach preparation of enantiomerically pure metaraminol or its salt.
Several synthetic methods have been reported in literature to prepare metaraminol or its salt; some of them have been incorporated here for reference.
US patent 10,087,136 discloses a process for the preparation of metaraminol bitartrate, which comprises the reaction of O-protected w-hydroxy benzaldehyde with nitroethane using copper-complex with a ligand, whereas the ligand being prepared starting from a non-naturally occurring isomer of (-)-(s,s) camphor to obtain metaraminol followed by conversion to metaraminol bitartrate using L-tartaric acid which is depicted as below:

wherein pg is hydrogen or a hydroxylprotecting group
In the examples given, the reaction has been carried out at -45°C to -40°C for 6 hours to 24 hours. The above process involves the use of expensive copper-ligand complex and very stringent reaction condition i.e. low temperature of -45°C to -40°C for 6 hours to 24 hours, which is very difficult to maintain; therefore it is not an attractive option to use for industrial scale.
A Chinese patent CN103739504 discloses another process for the preparation of metaraminol bitartrate, which comprises reaction of w-hydroxybenzaldehyde and nitroethane using a chiral catalyst system consisting of cinchona alkaloid, copper acetate hydrate and imidazole followed by reduction of nitro compound using hydrogen in the presence of palladium on carbon to obtain metaraminol. The

resulting metaraminol is then converted to metaraminol bitartrate using L(+)-tartaric acid which is depicted as below:



OH
N02 HO.
H2 HO.
HO.
^Y^H
I I Pd
N02

OH ■ Nl| = HOOC^CO°H
^J NH' 6H

Major drawbacks of this process are use of very expensive cinchona alkaloid catalyst, low reaction temperatures and low yields [about 7%], which makes the process unsuitable for industrial scale.
Another Chinese patent application CN107311875 discloses a process for the preparation of metaraminol bitartrate, which comprises cyclization of benzyl oxycarbonyl-Z-alanine to obtain (S)-iV-benzyloxycarbonyl-4-methyl-5-oxazolidine which is further reacted with Grignard reagent 3-benzyloxyphenylmagnesium bromide to obtain (4S)-JV-benzyloxycarbonyl-5-(3-(decyloxy)phenyl)-5-hydroxy-4-methyloxazolidine. The resulting product on ring opening produces (2S)-2-(benzyloxycarbonyl) amino-1-(3-benzyl oxyphenyl)-l-propanone followed by reduction using sodium borohydride to obtain (1R, 2S)-2-(benzyloxy)carbonyl)amino-l-(3-decyloxyphenyl)-l-propanol. The resulting product has been further deprotected to obtain metaraminol followed by preparation of metaraminol bitartartae which is depicted as below:


0^NpbZ
HO NCbz

Although patent discloses that high stereo-selectivity is obtained by steric hindrance effect, and intermediate compound 5 with high optical purity is formed when reducing carbonyl group, but no where in the description or in examples, the

chemical purity or enantiomeric purity has been mentioned; only yields are mentioned. In our hands, we have found that using sodium borohydride during reduction step does not lead to pure chiral reduced compound, the undesired isomer has also been found. Further during removal of Cbz or benzyl group using palladium on carbon in presence of hydrogen gas under pressure, the probability of formation of TV-methyl impurity is quite high, which may be difficult to remove.
An Indian patent application IN 201641006739 discloses a process for the preparation of metaraminol bitartrate, which comprises the reaction of 3-hydroxypropiophenone with n-butyl nitrite to obtain alpha-oximinoketone. The resulting compound is then reduced to obtain isomeric mixture of metaraminol followed by conversion to metaraminol bitartrate using L-tartataric acid. The metaraminol bitartrate is purified to obtain enantiomerically pure metaraminol bitartrate which is depicted below:

OH
HOOC^CO°H OH
The above process provides racemic metaraminol and diastereomers are separated thereafter. The separating enantiomers and diastereomers is known being difficult and expensive. The overall yield is 12-21% from oxime intermediate.
A new process has been developed for the preparation of metaraminol bitartrate, which involves the step of demethylation of (lS,2R)-2-hydroxy-2-(w-methoxyphenyl)-l -methylethyl amino-2,2-dimethylpropionate using a suitable demethylating agent yields in-situ formation of metaraminol which on purification by protection and deprotection method provides metaraminol and the resulting metaraminol is then converted into metaraminol bitartrate. It has been reported in our co-pending Indian patent application IN 201811040084.

However, during scale up it has been observed that when (lS,2R)-2-hydroxy-2-(w-methoxyphenyl)-1 -methylethylamino-2,2-dimethylpropionate is demethylated using boron tribromide, methyl bromide is generated as a side product along with metaraminol. The resulting metaraminol along with methyl bromide during work up when further quenched with a base, the side product methyl bromide reacts with metaraminol and forms w-methoxy metaraminol, which is carried forward as a tartrate salt on being reaction with tartaric acid during the conversion of metaraminol into metaraminol bitartrate and is very difficult to remove or reduced in the final active pharmaceutical ingredient (API) metaraminol bitartrate. Thus, control of w-methoxy metaraminol impurity during demethylation step is very crucial.
Like any synthetic compound, intermediate compounds can contain extraneous compounds or impurities that can come from many sources which may get carried forward to final API i.e. metaraminol bitartrate or may react to form other by products. These extraneous compounds in the intermediate may be unreacted starting materials, by products of the reaction, products of side reactions, or degradation products or different isomers. Impurities generated due to any reason in any API like metaraminol bitartrate are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The American Food and Drug Administration (FDA) as well as European medicament control offices require, according to the Q7A ICH (International Conference on Harmonization) guidance, that Active Pharmaceutical Ingredient (API) is freed from impurities to the maximum possible extent. The reason is achieving maximum safety of using the drug in the clinical practice. National inspection and control offices usually require that the content of an individual impurity in an API should not exceed the limit of 0.1%. All the substances (generally referred to as impurities) contained in an API over the limit of 0.1% should be isolated and characterized in accordance with the ICH recommendations. Q7A ICH guidance for manufacturers also states that process

impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratio, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
It is always advantageous to use intermediates of high purity which is free from the undesired impurities or such impurities should be present in acceptable amounts. The purity of the chemical compounds can be measured by chromatographic techniques such as high pressure liquid chromatography (HPLC). The control of impurities at intermediate step is always important, since impurities present in the intermediate stage may carried forward and may reacts further with further reagents and which results formation of new impurities along with main product.
As most of the prior art references are silent about purity of the metaraminol bitartrate and content of impurities and have their own advantages and disadvantages still there is a continuing need to develop an alternative process for the manufacture of pure metaraminol and its pharmaceutically acceptable salts. .
OBJECT OF THE INVENTION
The main object of the present invention is to provide a novel and industrially advantageous process for the preparation of pure metaraminol or pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide an industrially advantageous process for the preparation of enantiomerically pure metaraminol bitartrate.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel, efficient and industrially advantageous process for the preparation of enantiomerically pure metaraminol bitartrate of formula I,

Formula I OH
comprising the steps of:
a) reacting a 0-methylated hydroxyl compound of formula III;
OH
Formula III
with boron tribromide in a suitable solvent at a temperature of -10°C to
50°C;
b) diluting the reaction mixture using deminerahzed water at temperature 0°C to 65°C;
c) removing methyl bromide from the reaction mixture by a suitable method;
d) basifying the reaction mixture to a pH of 9 to 10 using a suitable base at temperature 0°C to 65°C;
e) isolating metaraminol of formula II; and
OH
Formula II
f) converting metaraminol of formula II to the compound of formula I.
According to another aspect the present invention provides a process for the preparation of enantiomerically pure metaraminol bitartrate of formula I,

Formula I NH2 O OH
comprising the steps of:
a) reacting 0-methylated hydroxyl compound of formula III;


Formula III

with boron tribromide in a suitable solvent at a temperature of -10°C to
50°C;
b) diluting the reaction mixture using demineralized water at temperature 0°C to 65°C;
c) removing methyl bromide from the reaction mixture by a suitable method;
d) basifying the reaction mixture to a pH of 9 to 10 using a suitable base at temperature 0°C to 65°C;
e) isolating metaraminol of formula II;
OH
Formula II NH2
f) reacting metaraminol of formula II with a suitable amino protecting agent
to obtain compound of the formula IV,
OH
Formula IV
wherein pg is amino protecting group; g) deprotecting the compound of formula IV using a suitable deprotecting
agent to obtain metaraminol compound of formula II; and h) treating metaraminol of formula II with L-tartaric acid in a suitable solvent
to obtain compound of formula!
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel, efficient and industrially advantageous process for the preparation of pure metaraminol or salt thereof from 0-methylated hydroxyl compound of formula III.

The term 'pure' as herein, can be referred as high chemical purity as well highly pure enantiomerically metaraminol or salt thereof and having purity of greater than 99.5% w/w and w-methoxy metaraminol impurity [namely 0-methyl metaraminol] less than 0.1%.
According to one aspect, the present invention provides a novel, efficient and industrially advantageous process for the preparation of enantiomerically pure metaraminol bitartrate of formula I from 0-methylated hydroxyl compound of formula III to reduce the amount of process related impurities to increase its purity.
The 0-methylated hydroxyl compound of formula III used as a starting material for the preparation of metaraminol bitartrate can be prepared by processes known in the art by the reaction of Z-alanine with di-tert-butyl dicarbonate followed by reaction with iV,0-dimethyl hydroxylamine hydrochloride to obtain 2-(N-methylmethoxyamino)-1 -methyl-2-oxoethylamino-2,2-dimethylpropionate, which on further reaction with w-bromoanisole and magnesium in presence of tetrahydrofuran results in to the (lS)-l-(w-anisoyl)-ethylamino-2,2-dimethyl propionate. The resulting product on reduction using aluminium isopropoxide in presence of toluene to obtain 0-methylated hydroxyl compound of formula III.
Generally the reaction of 0-methylated hydroxyl compound of formula III with boron tribromide can be carried out in the presence of a suitable solvent. Particularly the reaction of 0-methylated hydroxyl compound of formula III with boron tribromide can be accomplished at a temperature of about -20°C to about 50°C, preferably at -10°C to 35°C and it takes about 2 hours to about 20 hours preferably 11 hours to 13 hours for completion of reaction. The suitable solvent includes but not limited to aprotic solvent and can be selected from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform; ketones such as acetone and 2-butanone; esters such as ethyl acetate, methyl acetate; nitriles such as acetonitrile and benzonitrile; alkyl amides such as N,N-

dimethylformamide, jV,jV-diethylformamide, and iV-methylpyrrolidone and the like. Preferably, the solvent is dichloromethane.
The progress of the reaction can be monitored by suitable chromatographic techniques such as high pressure liquid chromatography (HPLC), gas chromatography (GC), ultra pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and the like.
During scale up of the reaction of 0-methylated hydroxyl compound of formula III with boron tribromide, as per the reaction, along with metaraminol, a side product methyl bromide is also formed. The resulting metaraminol along with methyl bromide during work up when quenched with base, the side product methyl bromide reacts with metaraminol and forms w-methoxy metaraminol impurity [namely 0-methyl metaraminol] as depicted below:


VQf
OH /
NH kj.. Boc

Br">,

B'Br
69
OH

MeBr 1 eq.

OH

The resulting metaraminol contains 0-methyl metaraminol of following formula:


0-methyl metaraminol
which on further conversion to tartrate salt results in the formation of metaraminol bitartrate along with impurity 0-methyl metaraminol bitartrate of following formula:

OH 9H Pi 0-methyl metaraminol bitartrate

It has been observed that once 0-methyl metaraminol impurity is generated, it is very difficult to remove or reduce in this step as well as 0-methyl metaraminol bitartrate impurity, in the final API metaraminol bitartrate. Thus control of impurity is very crucial at the demethylation step itself i.e. during conversion of 0-methylated hydroxyl compound of formula III to metaraminol.
After completion of reaction between 0-methylated hydroxyl compound of formula III and boron tribromide, the reaction mixture contains large amounts of suspended solid boron salts. It is reasonably possible that these salt particles can trap small amount of in-situ formed methyl bromide which reacts with in-situ generated metaraminol when methyl bromide is released with concomitant dissolution of the inorganic salts upon the addition of basic aqueous solution of sodium carbonate. Thus, to control the level of methyl bromide in reaction mixture, it is important to generate clear particle free solution of the reaction mixture so that methyl bromide trapped in the solid particles or dissolved in solution gets eliminated or evaporated from the reaction mixture during stirring at 10°C to 35°C, preferably at 25°C to 30°C. As per basic knowledge of organic chemistry, higher the basicity of the reaction mass, higher will be the propensity of the organic substrates to react with methyl bromide. On the other hand, under acidic conditions, the extent of reaction between the in-situ formed methyl bromide and metaraminol can be minimized.
Thus, to avoid impurity formation, instead of directly basifying the reaction mixture using a base, it is advantageous to initially dilute the reaction mixture with demineralized water to dissolve all the salts to obtain a clear highly acidic solution thereby creating conditions which will allow methyl bromide to evaporate from the reaction mixture.

Generally, after completion of the demethylation reaction, the reaction mixture
can be diluted with demineralized water. The dilution can be carried out using
10.0 volumes to 30.0 volumes of demineralized water, preferably using 15.0 to
25.0 volumes. The dilution can be carried out at temperature 0°C to 65°C,
preferably at 0°C to 40°C, more preferably at 0°C to 20°C. The removal of methyl
bromide can be facilitated by a suitable method such as by evaporation or by
raising the temperature of the reaction mixture with stirring or by applying
vacuum to the reaction mixture, or by purging the air or nitrogen in the reaction
mixture or by stirring the reaction mixture for longer time at 25°C to 30°C and the
like. Preferably methyl bromide can be removed by applying vacuum to the
reaction mixture. Generally, methyl bromide can be removed using the suitable
method as defined above, at temperature of 10°C to 35°C, preferably at 25°C to
30°C for 2 hours to 24 hours depending upon the method used. The resulting
reaction mixture free from methyl bromide [monitored by GC] can be further
basified using suitable base to attain a pH of around 9 to 10, preferably pH of 9.4
to 9.6. The basification can be carried out at temperature 0°C to 65°C, preferably
at 0°C to 40°C, more preferably at 0°C to 20°C. The suitable base can be selected
from inorganic base or organic base which may include but not limited to
hydroxides of alkali metal such as sodium hydroxide, potassium hydroxide, and
the like; carbonates of alkali metal such as sodium carbonate, potassium
carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the
like; ammonium hydroxide; organic base like tertiary amines such as
triethylamine, diisopropylethylamine, cyclohexyldimethylamine, N-
methylpiperidine, JV-methylpyrrolidine, iV-methylmorpholine and the like. Preferably, the base can be sodium carbonate.
The compound of formula II can be isolated by common isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof or can be used as such for the further reaction.
We have not found any reference wherein pure metaraminol or its salt preferably metaraminol bitartrate is prepared by demethylation of 0-methylated hydroxyl

compound of formula III using boron tribromide and removal of methyl bromide generated in situ has been carried out using a suitable method to control 0-methyl metaraminol impurity. Therefore, preparation of metaraminol or its salt preferably metaraminol bitartrate with control of impurities namely 0-methyl metaraminol and O-methyl metaraminol bitartrate forms the inventive part of the invention.
The resulting metaraminol of formula II can be converted to a suitable salt. Preferably metaraminol of formula II is converted to metaraminol bitartrate.
In an alternate way, the resulting metaraminol can be purified by employing any purification method such as crystallization, slurry wash, charcolization, base acid treatment, protection-deprotection, solvent/ anti solvent and the like.
In a specific embodiment, the metaraminol of formula II can be purified by protection-deprotection method to remove the inorganic salts. The protection of metaraminol of formula II can be carried out in presence of a suitable amino protecting agent. The suitable amino protecting agent can be selected from formyl, acetyl, trifluoroacetyl, fert-butoxycarbonyl (boc), trimethyl silyl (TMS), trimethylsilylethoxymethyl (SEM), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), pivaloyl, pyrrolidinylmethyl and the like. Preferably, the protecting agent is di-tert-butyldicarbonate.
The protection of metaraminol of formula II can be carried out in presence of protecting agent in a suitable solvent. The suitable solvent can be selected from alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiarybutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; ketones such as acetone. Preferably, the solvent is tetrahydrofuran.
The protection of metaraminol of formula II can be carried out in presence of a protecting agent and a solvent at temperature of about 15°C to about 55°C. Preferably, the reaction is carried out at a temperature of about 25°C to 50°C.

The protection of metaraminol of formula II can be carried out in presence of protecting agent and solvent for 1 hours to 3 hours. Preferably, the reaction is carried out for about 2 hours.
The compound of formula IV can be isolated by common isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof. Optionally, the resulting compound of formula IV can be purified by any suitable purification method, such as crystallization, slurry wash, and extraction with a suitable solvent to remove undesired impurities.
The protection of metaraminol of formula II using protecting reagent results compound of the formula IV. Since compound of the formula II contains two hydroxy and one amino group, during protection of metaraminol of formula II other all possible side products like mono O-protected, di-O-protected along with TV-protected or tri protected metaraminol or mixture thereof can also form in small amounts. This will not impact on the process, since during deprotection reaction all these and other mono O-protected, di-O-protected as well as mixed un¬protected compounds if formed may also get deprotected with mono protected compound and results in desired product that is metaraminol
In a specific embodiment of the present invention, the protection of metaraminol of formula II can be carried out wherein the protecting agent is di-tert-butyldicarbonate to prepare mono boc-protected compound of below formula IVA.
OH
TT jj - Formula IVA
—S HN I
It has been observed that during protection with di-fert-butyl dicarbonate, the diprotected compound wherein other boc group has been attached to OH group has also been formed in around 8% to 10% ratio along with desired mono-boc-

protected compound. The diprotected compound also gets deprotected during deprotection reaction and results in desired metaraminol.
The compound of formula IV and other protected derivatives can be deprotected using a suitable reagent depending upon the protecting agent used. The reagent can be selected from acid such as mineral acids or organic acids. The mineral acid is selected from the group comprising hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, boric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, or perchloric acid. The organic acid is selected from the group comprising formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, or an acidic ion exchange resin.
In a specific embodiment, the deprotection of boc-protected compound of formula IVA can be carried out in the presence of a suitable acid selected from the above list. Preferably, the acid is methanolic hydrogenchloride. The deprotection of compound of formula IVA can be carried out in presence of acid and a suitable solvent. The solvent can be selected from alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate. Preferably, the solvent is methanol. The deprotection of compound of formula IVA can be carried out in presence of acid and solvent at the temperature of about 0°C to about 55°C. Preferably, the reaction is carried out at a temperature of about 5°C to about 50°C. The deprotection of compound of formula IVA and its other protective derivatives can be carried out in presence of acid and solvent for about 8 hours to about 12 hours. Preferably, the reaction is carried out for about 10 hours. It is observed that di-boc protected compound also gets deprotected during treatment with acid and converts to metaraminol of formula II.
After completion of reaction, the reaction mixture can be cooled to a temperature of 0°C to 5°C and treated with a suitable base to achieve pH between 9 to 10 to

precipitate the compound of formula II. The resulting product can be isolated by conventional method such as filtration, decantation, centrifugation, or a combination thereof.
In an alternate way metaraminol of formula II can be purified by simply dissolving the compound in a suitable solvent and filtering off the insoluble inorganic salts and thereafter collecting the pure desired compound by distilling the solvent.
The pure metaraminol of formula II can be converted to metaraminol salts thereof by treating with a suitable acid. The conversion can be carried out at varying temperature depending upon the nature of acid used. Particularly, metaraminol of formula II can be converted to metaraminol bitartrate of formula I by treating with L-tartaric acid in a suitable solvent at a suitable temperature.
The suitable solvent can be selected from alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate and preferably ethanol is used. The salt preparation can be carried out at the temperature of about 10°C to about 70°C. Preferably, the reaction is carried out at a temperature of about 15°C to about 60°C and it takes about 1.5 hours to about 5 hours for completion of reaction. Preferably, the reaction can be carried out for 3.5 hours to 4.5 hours. After completion of reaction, the reaction mixture can be cooled to induce complete crystallization. The resulting product can be isolated by conventional method such as filtration, decantation, centrifugation, or a combination thereof. Optionally the resulting compound can be purified using a suitable technique such as crystallization, slurry wash, and solvent/ anti solvent crystallization; or combination thereof.
The resulting metaraminol bitartarate is obtained in high purity. Specifically metaraminol bitartarate is obtained is highly pure enantiomerically as well as chemically and displays purity of greater than 99.5% w/w; and preferably greater

than 99.8% w/w and more preferably greater than 99.9% w/w by HPLC containing 0-methyl metaraminol bitartrate impurity less than 0.1 % w/w preferably not detected level and chiral purity 99.9% and preferably 100%.
There are two chiral centers present in the metaraminol and hence four isomers (RS, SR, SS, RR) can be formed. Out of four isomers one isomer (RS) is desired. To control chirality, it is advantageous to involve use of Z-alanine for the preparation of metaraminol or salt thereof such as metaraminol tartrate.
The order and manner of combining the reactants at any stage of the process are not critical and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. The time required for the completion of the reaction may also vary widely, depending on multiple factors, notably the reaction temperature and the nature of the reagents and solvents employed. Wherever required, at intermediate stage or for the final compound, purification methods given can be repeated to achieve the desired purity. The progress of the reaction may be monitored by suitable chromatographic techniques such as high performance liquid chromatography (HPLC), gas chromatography (GC), ultra pressure liquid chromatography (UPLC) or thin layer chromatography (TLC).
The major advantage of present invention is to provide a novel, efficient and industrially advantageous process for preparation of pure metaraminol bitartrate of formula I by avoiding use of expensive catalysts or ligands and provide metaraminol tartrate of formula I in high yield and high purity chemically as well as enantiomerically and containing 0-methyl metaraminol bitartrate impurity less than 0.1% w/w.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples:
Example 1: Preparation of metaraminol bitartrate
To a stirred solution of (lS,2R)-2-hydroxy-2-(w-methoxyphenyl)-l-methyl ethylamino-2,2-dimethylpropionate (4.5 kg) in dichloromethane (36 L), freshly prepared solution of boron tribromide (16.02 Kg) in dichloromethane (9.0 L) was added slowly at -10°C to -5°C. The resulting reaction mixture was then stirred for 12 hours at 25°C to 30°C. After completion of reaction, [monitored by HPLC] which show absence of 0-methyl metaraminol impurity [monitored by GC], the reaction mixture was cooled to 0°C to 5°C. Thereafter pH was adjusted to 9.5 using 25% aqueous sodium carbonate solution by maintaining the temperature below 20°C. The layers were then separated and tetrahydrofuran (22.5 L) and di-fert-butyl dicarbonate (4.20 Kg) were then added to the aqueous layer followed by stirring for 2 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], dichloromethane (113.0 L) was added to the reaction mixture and the layers were separated. The aqueous layer was then extracted with dichloromethane (22.5 L). The resulting organic layers were combined and distilled out completely under vacuum to obtain residue. The resulting residue was then dissolved in dichloromethane (22.5 L) and washed with demineralized water (9.0 L x 2). The combined organic layer was then distilled out completely under reduced pressure to obtain boc-protected metaraminol. To a stirred solution of boc-protected metaraminol in methanol (4.5 L), 8-10% methanolic hydrogen chloride (18.0 L) was added at 5°C to 10°C and the reaction mixture was stirred at 25°C to 30°C for 10 hours. After completion of reaction [monitored by HPLC], the reaction mixture was cooled to 0°C to 5°C and pH was adjusted to 9.5 using 25% aqueous sodium carbonate solution. The solid material was then filtered off and washed with methanol (9.0 L x 2). The resulting filtrate was distilled out completely under reduced pressure and tetrahydrofuran (45 L) was added to the resulting residue and heated to 40°C to 45°C to obtain clear solution and then cooled to 5°C. Insoluble inorganic solid material was then filtered off followed by washing with tetrahydrofuran (11.25 L

x 2). To the filtrate, ethanol (9.0 L) was added and solvent was distilled out completely under vacuum.
The resulting residue was then dissolved in ethanol (18.0 L) followed by addition of activated carbon (0.45 Kg) at 20°C to 30°C. The reaction mixture was then cooled to 0°C to 5°C and filtered through celite, followed by washing with ethanol (9.0 L). The filtrate was then collected and to the filtrate, L-tartaric acid (2.40 kg) was added at 20°C to 30°C and the reaction mixture was stirred at 50°C to 60°C for 2 hours. Thereafter the reaction mixture was cooled to 0° to 10°C and stirred for 4 hours. The separated solid was filtered and washed with ethanol (13.5 L) to obtain the crude solid 2.92 Kg.
The resulting crude solid was then dissolved in demineralized water (5.84 L) and filtered to get particle free clear solution. Ethanol (116.8 L) was added to the resulting clear reaction at 25°C to 30°C. The resulting mass was then heated to 70°C to 80°C. The reaction mass was then cooled gradually to -10°C to -5°C and stirred for 8 hours. The reaction mass was then filtered and washed with ethanol (9.0 L) to obtain white crystalline solid. The resulting solid was suspended in methyl tert-buty\ ether (45.0 L) at 25°C and stirred for 1 hour under inert atmosphere. The resulting solid was filtered followed by washing with methyl tert-buty\ ether (9.0 L), and dried under vacuum at 75°C to 80°C for 12 hours to obtain 2.08 kg of title compound having purity 99.37% w/w and 0.63% of O-methyl metaraminol.
Example 2: Preparation of metaraminol bitartrate
To a stirred solution of (lS,2R)-2-hydroxy-2-(w-methoxyphenyl)-l-methyl ethylamino-2,2-dimethylpropionate (40.0 g) in dichloromethane (320 mL), freshly prepared solution of boron tribromide (142.5 g) in dichloromethane (80 mL) was added slowly at -10°C to -5°C. The resulting reaction mixture was then stirred for 12 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], the reaction mixture was diluted using demineralized water (800 mL) maintaining the temperature below 20°C. The vacuum was then applied to the reaction mass and stirred at 25°C to 30°C for 3 hours. Thereafter, the vacuum was released under

nitrogen atmosphere and dichloromethane (200 mL) was added to the reaction mass and cooled to 0°C to 5°C. Thereafter, pH of reaction mass was adjusted 9.5 using 25% aqueous sodium carbonate by maintaining the temperature below 20°C. The layers were separated and tetrahydrofuran (200 ml) and di-fert-butyl dicarbonate (37.23 g) were then added to the resulting aqueous layer and stirred for 2 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], dichloromethane (1000 ml) was added to the reaction mixture and the layers were separated. The resulting aqueous layer was then extracted with dichloromethane (200 mL). The combined organic layers were distilled out completely under reduced pressure. The resulting residue was then dissolved in dichloromethane (200 mL) and washed with demineralized water (80 mL x 2). The resulting organic layer was then distilled out completely under reduced pressure to obtain boc-protected metaraminol.
To a stirred solution of boc-protected metaraminol in methanol (40 mL), 9.0%> methanolic hydrogen chloride (160 mL) was added at 5°C to 10°C and the reaction mixture was then stirred at 25°C to 30°C for 10 hours. After completion of reaction [monitored by HPLC], the reaction mixture was cooled to 0°C to 5°C and pH was adjusted to 9.5 using 25% aqueous sodium carbonate solution. The resulting solid was then filtered off and washed with methanol (80 mL x 2). The resulting filtrate was then distilled out completely under reduced pressure and tetrahydrofuran (400 mL) was added to the residue and heated to 45°C to obtain clear solution and then cooled to 5°C. Insoluble inorganic solid material was then filtered off followed by washing with tetrahydrofuran (100 mL x 2). To the filtrate, ethanol (80 mL) was added and solvent was distilled out completely under vacuum. The resulting residue was then dissolved in ethanol (160 mL) followed by addition of activated carbon (4.0 g) at 20°C to 30°C. The reaction mixture was then cooled to 0°C to 5°C and filtered through celite, followed by washing with ethanol (80 ml). The filtrate was then collected and to the filtrate, L-tartaric acid (21.32 g) was added at 20°C to 30°C and the reaction mixture was stirred at 50°C to 60°C for 2 hours. Thereafter, the reaction mixture was cooled to 0°C to 10°C

and stirred for 4 hours. The separated solid was filtered and washed with ethanol (120 mL) to obtain the crude solid.
The resulting crude solid was then dissolved in water (80 mL) and filtered to get particle free clear solution. Ethanol (1600 ml) was then added to the resulting clear solution at 25°C to 30°C followed by heating at 70°C to 80°C. The resulting reaction mass was then cooled gradually to -10°C to -5°C and stirred for 8 hours. The reaction mass was then filtered and washed with ethanol (80 ml) to obtain solid. The resulting solid was then suspended in methyl tert-buty\ ether (400 mL) at 25°C and stirred for 1 hour under inert atmosphere. The reaction mass was then filtered and washed with methyl tert-buty\ ether (80 mL) and dried resulting solid under vacuum at 75°C to 80°C for 12 hours to obtain 22.0 g of the title compound having purity 99.95% w/w by HPLC and 0-methyl metaraminol impurty: Not detected and chiral purity 100%.
Example 3: Preparation of metaraminol bitartrate
To a stirred solution of (lS,2R)-2-hydroxy-2-(w-methoxyphenyl)-l-methyl ethylamino-2,2-dimethylpropionate (40.0 g) in dichloromethane (320 mL), freshly prepared solution of boron tribromide (142.5 g) in dichloromethane (80 mL) was added slowly at -10°C to -5°C. The resulting reaction mixture was then stirred for 12 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], the reaction mixture was diluted using demineralized water (800 mL) at temperature below 20°C. The vacuum was then applied to the resulting reaction mass at 25°C to 30°C and stirred for 3 hours. Thereafter, the vacuum was released under inert atmosphere and dichloromethane (200 mL) was added to the reaction mass and cooled to 0°C to 5°C. Thereafter, pH of reaction mass was adjusted to 9.5 using 25%) aqueous sodium carbonate maintaining the temperature below 20°C. The layers were then separated and tetrahydrofuran (200 ml) and di-fert-butyl dicarbonate (37.23 g) were then added to the resulting aqueous layer and stirred for 2 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], dichloromethane (1000 ml) was added to the reaction mixture and the layers were

separated. The resulting aqueous layer was then extracted with dichloromethane (200 mL). The combined organic layers were distilled out completely under reduced pressure. The resulting residue was then dissolved in dichloromethane (200 mL) and washed with demineralized water (80 mL x 2). The resulting organic layer was then distilled out completely under reduced pressure to obtain boc-protected metaraminol.
To a stirred solution of boc-protected metaraminol in methanol (40 mL), 9.0% methanolic hydrogen chloride (160 mL) was added at 5°C to 10°C and the reaction mixture was then stirred at 25°C to 30°C for 10 hours. After completion of reaction [monitored by HPLC], the reaction mixture was cooled to 0°C to 5°C and pH was adjusted to 9.5 using 25% aqueous sodium carbonate solution. The resulting solid was then filtered off and washed with methanol (80 mL x 2). The resulting filtrate was then distilled out completely under reduced pressure and tetrahydrofuran (400 mL) was added to the residue and heated to 40°C to 45°C to obtain clear solution and then cooled to 5°C to 10°C. Insoluble inorganic solid material was then filtered off followed by washing using tetrahydrofuran (100 mL x 2). To the filtrate, ethanol (80 mL) was added and solvent was distilled out completely under vacuum. The resulting residue was then dissolved in ethanol (160 mL) followed by addition of activated carbon (4.0 g) at 20°C to 30°C. The reaction mixture was then cooled to 0°C to 5°C and filtered through celite, followed by washing with ethanol (80 ml). The filtrate was then collected and to the filtrate, L-tartaric acid (21.32 g) was added at 20°C to 30°C and the reaction mixture was stirred at 50°C to 60°C for 2 hours. Thereafter, the reaction mixture was cooled to 0°C to 10°C and stirred for 4 hours. The separated solid was filtered and washed with ethanol (120 mL) to obtain the crude solid.
The resulting crude solid was then dissolved in water (80 mL) and filtered to get particle free clear solution. Ethanol (1600 ml) was then added to the resulting clear solution at 25°C to 30°C followed by heating at 70°C to 80°C. The resulting reaction mass was then cooled gradually to -10°C to -5°C and stirred for 8 hours. The reaction mass was then filtered and washed with ethanol (80 ml) to obtain

solid. The resulting solid was then suspended in methyl tert-butyl ether (400 mL) at 25°C and stirred for 1 hour under inert atmosphere. The reaction mass was then filtered and washed with methyl tert-butyl ether (80 mL) and dried resulting solid under vacuum at 75°C to 80°C for 12 hours to obtain 22.0 g of the title compound having purity 99.94% w/w by HPLC and 0-methyl metaraminol impurity: not detected.
Example 4: Preparation of metaraminol bitartrate
To a stirred solution of (lS,2R)-2-hydroxy-2-(w-methoxyphenyl)-l-methyl ethylamino-2,2-dimethylpropionate (4.5 Kg) in dichloromethane (36.0 L), freshly prepared solution of boron tribromide (16.0 Kg) in dichloromethane (9.0 L) was added slowly at -10°C to -5°C. The resulting reaction mixture was then stirred for 12 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], the reaction mixture was diluted using demineralized water (90.0 L) maintaining the temperature below 20°C. The vacuum was then applied to the resulting reaction mass at 25°C to 30°C and stirred for 3 hours. Thereafter, the vacuum was released under inert atmosphere and dichloromethane (22.5 L) was added to the reaction mass and cooled to 0°C to 5°C. Thereafter, pH of reaction mass was adjusted to 9.5 using 25%) aqueous sodium carbonate maintaining temperature below 20°C. The layers were then separated and tetrahydrofuran (22.5 L) and di-fert-butyl dicarbonate (4.2 Kg) were then added to the resulting aqueous layer and stirred for 2 hours at 25°C to 30°C. After completion of reaction [monitored by HPLC], dichloromethane (113.0 LI) was added to the reaction mixture and the layers were separated. The resulting aqueous layer was then extracted with dichloromethane (22.5 L). The combined organic layers were distilled out completely under reduced pressure. The resulting residue was then dissolved in dichloromethane (22.5 L) and washed with demineralized water (9.0 L x 2). The resulting organic layer was then distilled out completely under reduced pressure to obtain boc-protected metaraminol.
To a stirred solution of boc-protected metaraminol in methanol (4.5 L), 9.0%> methanolic hydrogen chloride (18.0 L) was added at 5°C to 10°C and the reaction

mixture was then stirred at 25°C to 30°C for 10 hours. After completion of reaction [monitored by HPLC], the reaction mixture was cooled to 0°C to 5°C and pH was adjusted to 9.5 using 25% aqueous sodium carbonate solution. The resulting solid was then filtered off and washed with methanol (9.0 L x 2). The resulting filtrate was then distilled out completely under reduced pressure and tetrahydrofuran (45 L) was added to the residue and heated to 40°C to 45°C to obtain clear solution and then cooled to 5°C to 10°C. Insoluble inorganic solid material was then filtered off followed by washing using tetrahydrofuran (11.25 L x 2). To the filtrate, ethanol (9.0 L) was added and solvent was distilled out completely under vacuum. The resulting residue was then dissolved in ethanol (18.0 L) followed by addition of activated carbon (0.45 Kg) at 20°C to 30°C. The reaction mixture was then cooled to 0°C to 5°C and filtered through celite, followed by washing with ethanol (9.0 L). The filtrate was then collected and to the filtrate, L-tartaric acid (2.4 Kg) was added at 20°C to 30°C and the reaction mixture was stirred at 50°C to 60°C for 2 hours. Thereafter, the reaction mixture was cooled to 0°C to 10°C and stirred for 4 hours. The separated solid was filtered and washed with ethanol (13.5 L) to obtain the crude solid.
The resulting crude solid was then dissolved in water (6.8 L) and filtered to get particle free clear solution. Ethanol (136.0 L) was then added to the resulting clear solution at 25°C to 30°C followed by heating at 70°C to 80°C. The resulting reaction mass was then cooled gradually to -10°C to -5°C and stirred for 8 hours. The reaction mass was then filtered and washed with ethanol (9.0 L) to obtain solid. The resulting solid was then suspended in methyl tert-buty\ ether (45.0 L) at 25°C and stirred for 1 hour under inert atmosphere. The reaction mass was then filtered and washed with methyl tert-buty\ ether (9.0 L) and dried resulting solid under vacuum at 75°C to 80°C for 12 hours to obtain 2.51 Kg of the title compound having purity 99.98% w/w by HPLC and 0-methyl metaraminol impurity : not detected.

WE CLAIM:
1. A process for the preparation of metaraminol bitartrate of formula I,


Formula I

comprising the steps of:
a) reacting a 0-methylated hydroxyl compound of formula III;
OH
.0. . . .
Formula III

with boron tribromide in a suitable solvent at a temperature of -10°C to
50°C;
b) diluting the reaction mixture using demineralized water at temperature 0°C to 65°C;
c) removing methyl bromide from the reaction mixture by a suitable method;
d) basifying the reaction mixture to a pH of 9 to 10 using a suitable base at temperature 0°C to 65°C;
e) isolating metaraminol of formula II; and
OH
Formula II NH2
f) converting metaraminol of formula II to the compound of formula I.
2. The process as claimed in claim 1, wherein in step a), the suitable solvent is selected from aprotic solvent.
3. The process as claimed in claim 1, wherein in step c), the suitable method is selected from methods such as by evaporation or by raising the temperature of the reaction mixture with stirring or by applying vacuum to the reaction mixture or by purging the air or nitrogen in the reaction mixture or by stirring the reaction mixture for longer time at 25°C to 30°C.

4. The process as claimed in claim 1, wherein in step d), the suitable base is inorganic base or organic base.
5. A process for the preparation of enantiomerically pure metaraminol bitartrate of formula I,


Formula I

comprising the steps of:
a) reacting a 0-methylated hydroxyl compound of formula III; OH
Formula III

with boron tribromide in a suitable solvent at a temperature of -10°C to
50°C;
b) diluting the reaction mixture using demineralized water at temperature 0°C to 65°C;
c) removing methyl bromide from the reaction mixture by a suitable method;
d) basifying the reaction mixture to a pH of 9 to 10 using a suitable base at temperature 0°C to 65°C;
e) isolating metaraminol of formula II;
OH
Formula II
f) reacting metaraminol of formula II with a suitable amino protecting agent
to obtain compound of the formula IV,
OH
Formula IV
wherein pg is amino protecting group;

g) deprotecting the compound of formula IV using a suitable deprotecting agent to obtain metaraminol compound of formula II; and
h) treating metaraminol of formula II with L-tartaric acid in a suitable solvent to obtain compound of formula I.
6. The process as claimed in claim 5, wherein in step a), the suitable solvent is selected from aprotic solvent.
7. The process as claimed in claim 5, wherein in step c), the suitable method is selected from methods such as by evaporation or by raising the temperature of the reaction mixture with stirring or by applying vacuum to the reaction mixture or by purging the air or nitrogen in the reaction mixture or by stirring the reaction mixture for longer time at 25°C to 30°C.
8. The process as claimed in claim 5, wherein in step d), the suitable base is selected from the inorganic base or organic base.
9. The process as claimed in claim 5, wherein step f), the suitable protecting agent is selected from formyl, acetyl, trifluoroacetyl, tertbutoxycarbonyl (boc), trimethyl silyl (TMS), trimethylsilylethoxymethyl (SEM), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), pivaloyl, pyrrolidinylmethyl.
10.The process as claimed in claim 5, wherein step g), the suitable deprotecting reagent is selected from acid such as mineral acids or organic acids.