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

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/benzylamine/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, 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 tartrate using L-tartaric acid which is depicted as below:
o
0 II Cu-Ligand Complex HQ

io>
NH2
P9' V^iT H + /"-N02

wherein pg is hydrogen or a hydroxy I protecting 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:



SNO2 HO.
HO.
OH
NO,

H2
Pd


OH
COOH
HOOC^V' OH

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 benzyloxycarbonyl-Z-alanine to obtain (S)-iV-benzyloxycarbonyl-4-methyl-5-oxazolidine which is further reacted with Grignard reagent to obtain (4S)-iV-benzyloxycarbonyl-5-(3-(decyloxy)phenyl)-5-hydroxy-4-methyloxazolidine. The resulting product on ring opening produces (2S)-2-(benzyloxycarbonyl) amino-1-(3-benzyloxyphenyl)-l-propanone followed by reduction using palladium on carbon 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:


O^NpbZ
HO NCbz

Although patent discloses that high stereoselectivity 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 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, the probability of formation of N-methyl impurity is quite high, which is 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-butylnitrile 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:
o o OH
N.0H ^ NH2

HO Jl n-butyl nitrile HQ II Reduction HO


OH
-^ ^COOH
il - Hoocr
} NH* 6H
The above process prepares racemic metaraminol and enantiomers are separated thereafter. The separating enantiomers and diastereomers is known being difficult and expensive. The overall yield is 12-21% from oxime intermediate.
In view of the above, number of processes are available for the preparation of metaraminol or salt thereof, which have their own advantages and disadvantages still there is a continuing need to develop alternative process for the manufacture of metaraminol and its pharmaceutically acceptable salts. Specifically there is a need in the art to develop a process for the preparation of enantiomerically pure metaraminol bitartrate, which obviates prior problems, such as separation of enantiomers and diastereomers in the final step, use of expensive catalyst and ligands; and very low reaction temperatures.

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.
5 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
10 bitartrate of formula I,

Formula I
UM
comprising the steps of:
a) reacting a O-methylated hydroxyl compound of formula III; OH
Formula III
with a suitable demethylating agent in a suitable solvent to obtain metaraminol of formula II; and


Formula II
15 b) 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,
6


Formula I

comprising the steps of:
a) reacting O-methylated hydroxyl compound of formula III; OH
Formula III
niN
with a suitable demethylating agent to obtain metaraminol of formula II;

5

Formula II NH2
b) 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;
c) deprotecting the compound of formula IV using a suitable deprotecting
agent to obtain metaraminol compound of formula II; and
d) treating metaraminol of formula II with L-tartaric acid in a suitable
10 solvent to obtain compound of formula I.
According to one another aspect the present invention provides a process for the preparation of metaraminol tartarate of formula I,

Formula I
UM
comprising the steps of: a) reacting L-alanine of formula V,
7

<-V
H2N r Formula V
OH
with di-tert-butyl dicarbonate to obtain compound of formula VI;

0 .
H I.
Formula VI OH
b) reacting compound of the formula VI with N, O-dimethylhydroxyl amine
hydrochloride of formula VII;
H Formula VII
HCI
to obtain compound of the formula VIII;
0

5

H J.
/vO" N Y Formula VIII
c) reacting m-bromoanisole with magnesium in solvent to obtain Grignard
reagent followed by reaction with compound of the formula VIII to obtain
a keto compound of the formula IX; 0
Formula IX

d) reducing keto compound of the formula IX using a suitable reducing agent
to obtain O-methylated hydroxyl compound of the formula III; OH
Formula III
10 e) reacting O-methylated hydroxyl compound of formula III with a suitable
demethylating agent to obtain metaraminol of formula II;

OH
Formula II
8

f) purifying metaraminol of formula II by protecting metaraminol with a
suitable amino protecting agent to obtain compound of the formula IV, OH
Formula IV
wherein pg is amino protecting group;
5 e) optionally purifying the compound of formula IV;
f) deprotecting compound of formula IV to obtain metaraminol compound of
formula II; and
g) converting metaraminol of formula II to metaraminol tartrate of formula I.
According to one another aspect the present invention provides a process for the
10 purification of metaraminol of formula II
OH
HO./. A/
rij I Formula II
^ NH2
comprising the steps of:
a) protecting metaraminol with a suitable amino protecting agent to obtain
compound of the formula IV, OH
Formula IV
wherein pg is amino protecting group;
15 b) optionally purifying the compound of formula IV;
c) deprotecting the compound of formula IV using a suitable deprotecting agent to obtain pure metaraminol of formula II.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel, efficient and industrially advantageous 20 process for the preparation of pure metaraminol or salt thereof from O-methylated hydroxyl compound of formula III.
9

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 O-methylated hydroxyl compound of
formula III. Generally the reaction of O-methylated hydroxyl compound of
5 formula III with a suitable demethylating agent can be carried out in the presence
of a suitable solvent. Particularly the reaction of O-methylated hydroxyl
compound of formula III with a suitable demethylating agent can be accomplished
at a temperature of about -20°C to about 50°C and it takes about 2 hours to about
20 hours for completion of reaction. The suitable demethylating agent can be
10 selected from boron tribromide, hydrobromic acid: acetic acid, sodium sulfide:
trimethylsilyl chloride, aluminium chloride: ethane thiol, aluminium chloride: sodium iodide, methanesulfonic acid: methionine or dodecanethiol and the like. Preferably boron tribromide can be used to demethylate O-methylated hydroxyl compound of formula III.
15 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, N,N-diethylformamide, and N-methylpyrrolidone and
20 the like. Preferably, the solvent is dichloromethane.
Preferably, the reaction can be carried out at a temperature of about -10°C to about 35°C and it takes about 11 to 13 hours for completion.
The progress of the reaction can be monitored by suitable chromatographic
techniques such as high pressure liquid chromatography (HPLC), gas
25 chromatography (GC), ultra pressure liquid chromatography (UPLC), thin layer
chromatography (TLC) and the like.
After completion of the reaction, the reaction mixture can be is quenched with a suitable base to attain a pH of around 9 to 10. The suitable base can be selected from inorganic base or organic base which may include but not limited to the
10

group comprising of inorganic base like 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
5 amines such as triethylamine, diisopropylethylamine, , cyclohexyldimethylamine,
N-methylpiperidine, N-methylpyrrolidine, N-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,
10 or a combination thereof or can be used as such for the further reaction.
We have not found any reference wherein preparation of metaraminol has been provided using O-methylated hydroxyl compound of formula III, therefore preparation of metaraminol from O-methylated hydroxyl compound of formula III forms the inventive part of the invention.
15 The resulting metaraminol of formula II can be converted to a suitable salt.
Preferably metaraminol of formula II is converted to metaraminol tartrate.
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/antisolvent and the like.
20 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, tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),
25 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.
11

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 5 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 the temperature of about 15°C to about 55°C. 10 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 15 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. In a specific embodiment of the present invention, the 20 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 J, Formula IVA
>x HN
It has been observed that during protection with di-tert-butyl dicarbonate, the
diprotected compound wherein other boc group has been attached to OH group
25 has also been formed in around 8% to 10% ratio along with desired mono-boc-
protected compound. The diprotected compound also get deprotectesd during
12

deprotection reaction and results in desired metaraminol. The conversion of di-boc-protected compound to metaraminol also forms an inventive part of invention.
The compound of formula IV can be deprotected using a suitable reagent
depending upon the protecting agent used. The reagent can be selected from acid
5 such as mineral acids or organic acids and in the presence of base too. 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
10 acid, p-toluenesulphonic acid, or an acidic ion exchange resin. The base can be
selected from piperidine, piperazine, morpholine, diethyl amine, ammonia, sodium hydroxide, cesium fluoride, tetrabutyl ammonium fluoride and the like.
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
15 list. Preferably, the acid is methanolic hydrochloride. 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-
20 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 can be carried out in
25 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 get 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
30 of 0°C to 5°C and treated with a suitable base to achieve pH between 9 to 10 to
13

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
5 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 purification of metaraminol using protection–deprotection method further forms the inventive part of the invention
10 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.
15 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
20 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
25 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.
14

The resulting metaraminol bitartarate is obtained in high yields and high purity.
Specifically metaraminol bitartarate is obtained in 60% to 75% from O-
methylated hydroxyl compound of formula III and is highly pure enantiomerically
as well as chemically and have purity of greater than 99.5% w/w and preferably
5 greater than 99.8% w/w and more preferably greater than 99.9% w/w by HPLC
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 L-alanine for the
10 preparation of metaraminol or salt thereof such as metaraminol tartrate.
The starting material O-methylated hydroxyl compound of the formula III can be prepared by using the processes known in the art, or by the process as described herein by staring from L-alanine and m-bromoanisole. L-alanine and m-bromoanisole used as starting materials are commercially available.
15 Generally, L-alanine of the formula V is protected with a suitable amino
protectiong agent. Preferably L-alanine can be reacted with di-tert-butyl dicarbonate in presence of base. Preferably, a suitable base can be selected from inorganic base which may include but not limited to the group like hydroxides of alkali metal or alkaline earth metal such as sodium hydroxide, potassium
20 hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and the like;
carbonates of alkali metal such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; Preferably base used is sodium hydroxide.
The reaction of L-alanine of the formula V with di-tert-butyl dicarbonate and base
25 can be carried out in presence of solvent at the temperature of about -5°C to about
40°C for 8 hours to 15 hours. Preferably, the reaction is carried out at a temperature of about 0°C to about 30°C in tetrahydrofuran for about 12 hours.
15

After completion of the reaction, the compound of Formula VI can be isolated by common isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof.
The reaction of compound of the formula VI with N,O-dimethylhydroxyl amine
5 hydrochloride of the formula VII can be carried out in presence of organic base
like tertiary amines such as triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like. Preferably, the base is triethylamine. The reaction of compound of the formula VI with N,O-dimethylhydroxyl amine hydrochloride of the formula VII can be
10 carried out in presence of coupling agent. Preferably, the coupling agent is
hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride The reaction of compound of the formula VI with N,O-dimethylhydroxyl amine hydrochloride of the formula VII can be carried out in presence of solvent like halogenated aliphatic hydrocarbons such as
15 dichloromethane, dichloroethane, chloroform or carbon tetrachloride. Preferably,
the solvent is dichloromethane The reaction of compound of the formula VI with N,O-dimethylhydroxyl amine hydrochloride of the formula VII can be carried at the temperature of about -5°C to about 40°C for about 10 hours to about 15 hours. Preferably, the reaction is carried out at a temperature of about 0°C to about 30°C
20 for about 12 hours. The compound of formula VIII can be isolated by common
isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof.
The reaction of m-bromoanisole with magnesium can be carried out in a suitable solvent such as tetrahydrofuran, The reaction of m-bromoanisole with magnesium
25 can be carried at the temperature of about 15°C to about 70°C. Preferably, the
reaction is carried out at a temperature of about 20°C to about 70°C. The reaction of m-bromoanisole with magnesium can be carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 2 hours to 3 hours. The reaction of compound of the formula VIII with Grignard reagent can be carried
30 out at the temperature of about -20°C to about 25°C. Preferably, the reaction is
16

carried out at a temperature of about -10°C to about 20°C. The reaction of compound of the formula VIII with Grignard reagent can be carried out for 2 hours to 5 hours. Preferably, the reaction is carried out for about 3 to 4 hours.
The keto compound of formula IX can be isolated by common isolation
5 techniques such as extraction, crystallization, precipitation, filtration, decantation,
centrifugation, or a combination thereof.
The reduction of keto compound of the formula IX can be carried out in presence
of a suitable reducing agent. Preferably, the reducing agent can be aluminium
isopropoxide. The reduction of keto compound of the formula IX can be carried
10 out in presence of solvent. Preferably, the solvent is isopropanol. The reduction of
keto compound of the formula IX can be carried at the temperature of about 10°C to about 70°C. Preferably, the reaction is carried out at a temperature of about 45°C to about 70°C.
The reduction of keto compound of the formula IX can be carried out for 3 hours
15 to 6 hours. Preferably, the reaction is carried out for about 4 hours to 5 hours.
After completion of reaction, the reaction mass is diluted with water and layers are
separated. The O-methylated hydroxyl compound of formula III can be isolated by
common isolation techniques such as extraction, crystallization, precipitation,
filtration, decantation, centrifugation, or a combination thereof. As used herein the
20 term “conventional methods for the isolation of intermediates as well as final
product” may be varied depending upon the nature of the reactions, nature product
of the reaction, medium of the reaction and the like. The suitable conventional
methods can be selected amongst but not limited to distillation of the solvent,
addition of water to the reaction mixture followed by extraction with water
25 immiscible solvents, removal of the insoluble particles from the reaction mixture, if
present, by filtration or centrifugation or by decantation, addition of water immiscible organic solvent, addition of a solvent to the reaction mixture which precipitate the product, neutralizing the reaction mixture with a suitable acid or base whichever is applicable.
17

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
5 may be combined in any order. The time required for the completion of the
reaction may also vary widely, depending on many 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
10 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 metaraminol bitartrate of
15 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.
While the present invention has been described in terms of its specific aspects and
embodiments, certain modifications and equivalents will be apparent to those
20 skilled in the art and are intended to be included within the scope of the present
invention.
Examples:
Example 1: Preparation of 2-(N- methylmethoxyamino)-1-methyl-2-oxoethyl amino-2,2-dimethylpropionate
25 To a stirred solution of L-alanine (1.0 Kg) in distilled water (3.0 L), sodium
hydroxide solution (0.67 Kg in 3.0 L distilled water) wasadded at 0°C to 5°C. To the resulting reaction mixture, a solution of di-tert-butyl dicarbonate (2.94 Kg) in tetrahydrofuran (2.0 L) was added at 0°C to 5°C. The reaction mixture was then stirred at 20°C to 30°C for 12 hours. After completion of reaction, [monitored by
18

HPLC], methyl tert-butyl ether (10.0 L) and distilled water (1.0 L) were added
and the reaction mixture was stirred for further 30 minutes and thereafter allowed
to settle. The aqueous layer was separated and washed with methyl tert-butyl ether
(3.0 L). The aqueous layer was then cooled to 0°C to 5°C and pH was adjusted to
5 4.5 using 8N hydrochloric acid solution. Dichloromethane (6.0 L) was then added
to the reaction mixture at 0°C to 5°C and the layers were separated. The aqueous layer was again extracted with dichloromethane (4.0 L) at 0°C to 5°C. Both the organic layers were combined and distilled out completely under reduced pressure to obtain an oily residue.
10 To the resulting residue, dichloromethane, (10.0 L) triethylamine (2.27 Kg) and
hydroxybenzotriazole (1.21 Kg) were added slowly at 0°C to5°C. Thereafter 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.36 Kg) and N,O-dimethyl hydroxylamine hydrochloride (1.20 kg) were added slowly and the temperature was maintained below 15°C. The temperature of reaction mixture was
15 raised to 20°C to 30°C and stirred for further 12 hours. After completion of the
reaction, distilled water (7.0 L) was added to the reaction mixture and the layers were separated. The aqueous layer was again extracted with dichloromethane (3.0 L). Both the organic layers were combined and hydrochloric acid (0.45 L conc. hydrochloric acid in 4.55 L distilled water) was added to it. The resulting mixture
20 was filtered to remove undissoved particles and filtrate was allowed to settle. The
organic layer was separated followed by washing with distilled water (8 L x 3) and distilled out completely under reduced pressure to obtain the solid compound. The resulting solid was suspended in dichloromethane (0.8 L) and methyl tert-butyl ether (7.2 L) at 20°C to 30°C and stirred for about 20 minutes. The solid was
25 then filtered and washed with methyl tert-butyl ether (4.0 L). The resulting solid
was suck dried and above purification was repeated by using dichloromethane (0.5 L) and methyl tert-butyl ether (4.5 L). The separated solid was then filtered and washed with methyl tert-butyl ether (2.0 L) followed by drying under vacuum at 45°C to 50 °C for 12 hours to obtain 2.0 Kg of the title compound having purity
30 99.5% w/w by HPLC.
19

Example 2: Preparation of (1S)-1-(m-anisoyl)-ethylamino-2,2-dimethyl propionate
To a solution of tetrahydrofuran (7.0 L) and iodine (0.02 g), dried magnesium
turnings (0.52 Kg) were added. Parallel a solution of 3-bromoanisole (4.03 Kg) in
5 tetrahydrofuran (5.0 L) was prepared and 10-15% of 3-bromoanisole solution was
added drop wise to the above reaction mixture at 25°C to 30°C with stirring to
initiate the Grignard reaction. After the initiation of reaction, the reaction mixture
was heated to reflux temperature and rest of 3-bromoanisole solution was added
drop wise to the reaction mixture and stirred for 3 hours at 65°C to 70°C to obtain
10 the reagent.
The reagent prepared as above, was then cooled to -10°C to -5°C and 2-(N-
methylmethoxyamino)-1-methyl-2-oxoethylamino-2,2-dimethylpropionate (1.0
Kg) was added at -10°C to -5°C, maintaining the temperature below 15°C during addition. After complete addition, the reaction mixture was stirred for 3 hours to 4
15 hours at 10°C to15°C. Thereafter on completion of reaction [ monitored by
HPLC], ammonium chloride solution (1.0 Kg ammonium chloride in 10.0 L distilled water) was added drop wise and maintained the temperature below 35°C. Sodium chloride (1.0 Kg) was then added into the reaction mixture and stirred for 30 minutes. The layers were separated and the aqueous layer was again extracted
20 with ethyl acetate (5.0 L). Both the organic layers were combined and distilled out
under reduced pressure. Isopropanol (2.0 L) was added to the resulting residue and distilled out completely under vacuum. The resulting residue was then dissolved in isopropanol (1.0 L) followed by addition of distilled water (2.0 L) and stirred for 1 hour to 2 hours at 0°C to 5°C to obtain the solid. The resulting solid was
25 filtered and washed with a mixture of isopropanol-distilled water [isopropanol
(6.0 L)/ distilled water (6.0 L)]. Repeated the same process again using chilled isopropanol (3.0 L)/distilled water (3.0 L) mixture to obtain the solid. The resulting solid was dried under vacuum for 12 hours at 45°C to 50°C to obtain 0.86 Kg title compound having purity of 99.5% w/w by HPLC.
20

Example 3: Preparation of (1S,2R)-2-hydroxy-2-(m-methoxyphenyl)-1-methylethylamino-2,2-dimethylpropionate
Aluminium isopropoxide (0.36 Kg) was added to a stirred solution of (1S)-1-(m-
anisoyl)-ethylamino-2,2-dimethylpropionate (1.0 Kg) in toluene (4.0 L) and
5 isopropanol (2.7 L), at 20°C to 30°C. The resulting reaction mixture was heated
at 55°C to 60°C for 4 -5 hours. After completion of reaction,[ monitored on HPLC], the reaction mixture was cooled to 20°C to 30°C, distilled water (10.0 L) was added and the layers were separated. The aqueous layer was again extracted with ethyl acetate (5.0 L) and both the organic layer were combined and
10 distilled out completely under reduced pressure. Isopropanol (1.5 L) was added to
the resulting residue and temperature was raised to 40°C to 45°C to obtain a clear solution. The resulting solution was cooled to 20°C followed by addition of mixture of 1:1 distilled water/ n-hexane (8.0 L/8.0 L) and then stirred at 15°C to 20°C for 4 hours. The separated solid was filtered, washed with n-hexane (4.0 L),
15 and dried under vacuum at 40°C to 45°C for 12 hours to obtain 0.95 Kg of title
compound having purity of 99.5% w/w by HPLC and 100% chiral purity.
Example 4A: Preparation of metaraminol bitartrate
To a stirred solution of (1S,2R)-2-hydroxy-2-(m-methoxyphenyl)-1-methyl ethylamino-2,2-dimethylpropionate (20.0 g) in dichloromethane (200.0 L), boron
20 tribromide (20.26 ml) was added slowly at 20°C to 25°C. The resulting reaction
mixture was then stirred for 5 hours at 25°C to 30°C. After completion of reaction, [monitored by HPLC], the reaction mixture was quenched by addition of aqueous sodium hydroxide (10.0 g sodium hydroxide in 20.0 mL distilled water ) at 0°C to 5°C, and the pH was adjusted to 9.4 to 9.6. The layers were then separated and
25 aqueous layer was distilled out completely under vacuum to obtain residue. The
resulting residue was suspended in isopropanol (50.0 ml) and stirred for 15 minutes at 45°C to 50°C. The resulting mixture was filtered and process is repeated twice to remove solid. The resulting filtrate was distilled out completely under vacuum at 45°C to 50°C to obtain the residue. The resulting residue was
21

then suspended in ethyl acetate (100.0 ml) and stirred for 15 minutes to 20 minutes at 45°C to 50°C followed by filtration. The resulting filtrate was then distilled out under vacuum at 45°C to 50°C to obtain crude metaraminol as oil having purity 94.19% w/w by HPLC.
5 To a solution of crude metaraminol, obtained as above, in ethanol (100.0 ml), L-
tartaric acid (10.76 g) was added at 65°C to 70°C. The mixture was then stirred for 3 hours and resulting solid was filtered and washed with isopropanol (100.0 ml) followed by drying under vacuum at 45°C to 50°C for 12 hours to obtain 14.4 g title compound having purity 99.5% w/w by HPLC and chiral purity 100%.
10 Example 4B: Preparation of metaraminol bitartrate
To a solution of O-methylated hydroxyl compound of the formula III (0.35 Kg) in dichloromethane (2.8 L), freshly prepared solution of boron tribromide (1.25 Kg) in dichloromethane (0.7 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
15 of reaction, the reaction mixture was quenched by addition of 25% aqueous
sodium carbonate solution at 0°C to 5°C, (maintaining the temperature below 20°C) and thereafter the pH was adjusted to 9.4-9.6. The layers were then separated and to the aqueous layer, tetrahydrofuran (1.75 L) and di-tert-butyl dicarbonate (0.33 Kg) were then added and stirred for 2 hours at 25°C to 30°C.
20 After completion of the reaction, dichloromethane (8.75 L) was added to the
reaction mixture and the layers were separated. The aqueous layer was again extracted with dichloromethane (1.75 L), both the organic layers were combined and distilled out completely under vacuum. The resulting residue was dissolved in dichloromethane (1.75 L) and washed with distilled water (0.7 L x 2). The organic
25 layer was then distilled out completely under reduced pressure to obtain boc-
protected metaraminol.
To a stirred solution of boc-protected metaraminol in methanol (0.35 L), 8-10% methanolic hydrogen chloride (1.4 L) was added at 5°C to 10°C and the reaction
22

mixture was stirred at 25°C to 30°C for 10 hours. After completion of reaction,
[monitored on HPLC], the reaction mixture was cooled to 0°C to 5°C and pH was
adjusted to 9.4 to 9.5 using 25% aqueous sodium carbonate solution. The solid
material was then filtered off and washed with methanol (0.7 L x 2). The resulting
5 filtrate was then distilled out completely under reduced pressure and
tetrahydrofuran (3.5L) was added to the resulting residue and heated to 40°C to 45°C to obtain clear solution. Insoluble inorganic solid material was then filtered off followed by washing using tetrahydrofuran (0.88 L x 2). To the filtrate, ethanol (0.7 L) was added and solvent was distilled out completely under vacuum.
10 The resulting residue was then dissolved in ethanol (0.7 L) followed by addition
of activated carbon (0.035 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 (0.7 L). The filtrate was then collected and to the filtrate, L-tartaric acid (0.19 Kg) was added at 20°C to 30°C and the reaction mixture was stirred at 50°C to 60°C
15 for 2 hours. Thereafter the reaction mixture was cooled to 0°C - 10°C, stirred for 4
hours; the separated solid was filtered and washed with ethanol (1.05 L) to obtain the title compound having purity 99.5% w/w by HPLC and 100% chiral purity.
Example 4C: Preparation of metaraminol bitartrate
To a solution of O-methylated hydroxyl compound of the formula III (1.0 Kg) in
20 dichloromethane (8.0 L), freshly prepared solution of boron tribromide (3.56 Kg)
in dichloromethane (2.0 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, the reaction mixture was quenched by slow addition of 25% aqueous
sodium carbonate solution at 0°C to 5°C and the pH was adjusted to 9.4-9.6. The
25 layers were then separated and to the aqueous layer, tetrahydrofuran (5.0 L) and
di-tert-butyl dicarbonate (0.93 Kg) were then added and stirred for 2 hours at 25°C to 30°C. After completion of the reaction, dichloromethane (25 L) was added to the reaction mixture and the layers were separated. The aqueous layer was again extracted with dichloromethane (5.0 L) and both the organic layers
23

were combined and distilled out completely under vacuum. The resulting residue was dissolved in dichloromethane (5.0 L) and washed with distilled water (2.0 L x 2). The organic layer was then distilled out completely under reduced pressure to obtain a mixture of boc-protected metaraminol and di-boc-protected metaraminol.
To a stirred solution of boc-protected metaraminol in methanol (1.0 L), 8-10% methanolic hydrogen chloride (4.0 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 on HPLC], the reaction mixture was cooled to 0°C to 5°C and pH was adjusted to 9.4 -9.5 using 25% sodium carbonate solution. The solid material was then filtered off and washed with methanol (2.0 L x 2). The resulting filtrate was then distilled out completely under reduced pressure and tetrahydrofuran (10.0 L) was added to the resulting residue and heated to 40°C to 45 °C to obtain clear solution. Insoluble inorganic solid material was then filtered off followed by washing using tetrahydrofuran (2.5 L x 2). To the filtrate, ethanol (2.0) was added and solvent was distilled out completely under vacuum. The resulting residue was then dissolved in ethanol (2.0 L) followed by addition of activated carbon (0.1 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 (2.0 L). The filtrate was then collected and to the filtrate, L-tartaric acid (0.533 Kg) was added at 20°C to 30°C and the reaction mixture was stirred for at 50°C to 60°C for 2 hours. Thereafter the reaction mixture was cooled to 0°C to 10°C, stirred for 4 hours; the separated solid was filtered and washed with ethanol (3.0 L) to obtain crude solid having purity 99.5% w/w by HPLC and 100%) chiral purity.
The resulting solid was purified with ethanol (40 L): water (2 L) to obtain pure white crystalline solid. The resulting solid was suspended in methyl tert-buty\ ether (10.0 L) at 25°C, stirred for 1 hour under inert atmosphere, filtered followed by washing with methyl tert-buty\ ether (2.0 L), and dried under vacuum at 75°C to 80°C for 12 hours to obtain 0.85 Kg of the title compound having purity 99.9%> w/w by HPLC and 100% chiral purity.

WE CLAIM:

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
Formula III
niN I
with a suitable demethylating agent in a suitable solvent to obtain metaraminol of formula II;

Formula II ^ NH2
and
b) treating metaraminol of formula II with L-tartaric acid in a suitable solvent to obtain compound of formula!
The process as claimed in claim 1, wherein in step a), the demethylating agent is selected from boron tribromide, hydrobromic acid: acetic acid, sodium sulfide: trimethylsilyl chloride, aluminium chloride: ethane thiol, aluminium chloride: sodium iodide, methanesulfonic acid: methionine or dodecanethiol; the suitable solvent is selected from aprotic solvent.
The process as claimed in claim 2, preferably the demethylating agent is boron tribromide.

4. A process for the preparation of enantiomerically pure metaraminol bitartrate of formula I,

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

Formula III
niN I
with a suitable demethylating agent to obtain metaraminol of formula II;

Formula II NH2
b) 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;
c) deprotecting the compound of formula IV using a suitable deprotecting agent to obtain metaraminol compound of formula II; and
d) treating metaraminol of formula II with L-tartaric acid in a suitable solvent to obtain compound of formula!
A process for the preparation of metaraminol tartarate of formula I,
HO^
Formula I

comprising the steps of:

\{
a) reacting L-alanine of formula V,
Formula V OH
H2N' with di-fert-butyl dicarbonate to obtain compound of formula VI;
0

H I,
Formula VI OH

b) reacting compound of the formula VI with N, O-dimethylhydroxyl amine hydrochloride of formula VII;
H Formula VII
HCI to obtain compound of the formula VIII;

/-^0

Formula VIII

c) reacting w-bromoanisole with magnesium in solvent to obtain Grignard
reagent followed by reaction with compound of the formula VIII to obtain
a keto compound of the formula IX; 0
Formula IX
d) reducing keto compound of the formula IX using a suitable reducing agent
to obtain 0-methylated hydroxyl compound of the formula III; OH
Formula III

e) reacting 0-methylated hydroxyl compound of formula III with a suitable
demethylating agent to obtain metaraminol of formula II;
OH
H0V\A/
y if i Formula II
^ NH2
f) reacting metaraminol of formula II with a suitable amino protecting
agent to obtain compound of the formula IV, OH
y\\ L Formula IV
^ HN
i
pg
wherein pg is amino protecting group;
g) optionally purifying the compound of formula IV;
h) deprotecting compound of formula IV using a suitable deprotecting agent
to obtain metaraminol compound of formula II; and i) converting metaraminol of formula II to metaraminol tartrate of formula I.
The process as claimed in claim 5, wherein step e) the suitable demethylating agent is selected from boron tribromide, hydrobromic acid: acetic acid, sodium sulfide: trimethylsilyl chloride, aluminium chloride: ethane thiol, aluminium chloride: sodium iodide, methanesulfonic acid: methionine or dodecanethiol. The process as claimed in claim 5, wherein step f) the suitable amino protecting agent is selected from formyl, acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), trimethylsilylethoxymethyl (SEM), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), pivaloyl, pyrrolidinylmethyl.
The process as claimed in claim 5, wherein step h) the suitable deprotecting reagent is selected from acid such as mineral acids or organic acids and a suitable base.

9. A process for the purification of metaraminol of formula II OH
X if i Formula II
^ NH2
comprising the steps of:
d) protecting metaraminol with a suitable amino protecting agent to obtain
compound of the formula IV, OH
y || i Formula IV
^ HN
i
pg
wherein pg is amino protecting group;
e) optionally purifying the compound of formula IV;
f) deprotecting compound of formula IV using a suitable deprotecting agent in a suitable solvent to obtain pure metaraminol compound of formula II.
. The process as claimed in claim 9, wherein step a) the suitable amino protecting agent is selected from formyl, acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), trimethylsilylethoxymethyl (SEM), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), pivaloyl, pyrrolidinylmethyl; in step c) the suitable deprotecting reagent is selected from acid and base.