• Field of the Invention:
The present invention is concerned with the process for the production of novel intermediates and their preparation, which are used as an important intermediates for the manufacture of Metyrosine. Metyrosine, is chemically known as (2S)-2-Amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid of the formula-(1).

Metyrosine is an inhibitor of tyrosine hydroxylase, has anti-hypertensive activity and is widely used for the treatment of pheochromocytoma (Merck Index, Volume-14, page.1062, 6162, Agric.Biol.Chem., 62(9), 2349-2350, 1988.). It act as inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is used to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma. (Martindale, The Extra Pharmacopoeia, 30th ed). The activity of Metyrosine is apparently rest with (S)-Metyrosine and (R)-Metyrosine is completely inactive. It is therefore all the more important to develop an effiClent and economically viable asymmetric synthesis route for (S)-Metyrosine without any Classical resolution process. The novel intermediates which are subject of the present invention are compounds of having the general formula-(2) and (3).


Where in R1 to R5= H, Cl, Br, and F, R6 = Isobutyl, t-butyl group, R7= Trifluoroacety, acetyl and benzoyl groups and R8= Methyl, ethyl and isopropyl groups etc.,

• Background of the Invention:
Various methods for the production of Metyrosine are known from the literature.
For example in US: patent No 2868818, disClosed the preparation of Metyrosine
as shown in the reaction Schemd-1.
The process disClosed in the said patent involves the amine protection of a-
methyl phenylalanine of the formula -(4) with dichloroacetylchloride of the formula
-(5) to give dl-a-methyl-N-dichloroacetyl phenylalanine of the formula -(6). Which
is further nitrated with nitric acid followed hydrogenation in the presence of
platinum oxide to give dl-a-methyl-N-dichloroacetyl-p-(4-aminbphenyl)-alanine of
the formula-(7) which is further reacted with Sodium nitrite in presence of Sulfuric
acid followed by heating with mineral acid to give racemic Metyrosine of the
formula-(1).

Scheme-1:

The general process disClosed in the above patent suffers from several drawbacks, espeClally from commerClal point of view. They are (i) the use of highly expensive Platinum oxide and toxic chemicals like dichloroacetylchloride, sodium nitrite, nitric acid and (ii) the required final step of optical resolution to get pure Metyrosine make the process more cumbersome and tedious. Another synthetic route has been disClosed in the US patent No 4508921 for the preparation of Metyrosine using the following synthetic route as shown in

Scheme-2.
The disClosed process involves reaction of (S)-N,0-bis-(carbobenzyloxy)tyrosine of the formula-(8) with benzaldehyde of the formula-(9) in the presence of p-toluenesulfonic acid as catalyst to give a mixture of trans: Cls 3-carbobenzyloxy-4-[(4-carbobenzyloxyphenyl)methyl]-2-phenyloxazolidinone of the formula-(10).

After the separation of the isomers by using Si-gel column chromatography pure Cls isomer is further reacted with methyl iodide in the presence of KHMDS to give Cls-3-carbobenzyloxy-4-[(4-carbobenzyloxyphenyl)methyl]-4-methyl-2-phenyloxazolidinoneof the formula-(11), which is further converted into Metyrosine compound of the formula-(1) by subsequent reaction with Sodium hydroxide in methanol followed by catalytic hydrogenation with Pd/C.
Scheme-2:

The general process disClosed in the above patent is uneconomical espeClally because of the unavoidably complicated process involving the separation of Cls and trans isomers by Si-gel column chromatography and catalytic hydrogenation, separation of isomers formed and isolating pure isomer by Si-gel column chromatography. Employment of column chromatography in a commerClal scale is difficult and therefore the process is not suitable for commerClal scale production.

Further Daniel Obrecht et.al., Helv.Chim.Acta., 78,1567-1587,(1995) have disClosed a asymmetric synthesis of Metyrosine using the following synthetic route as shown in

Scheme-3.

This approach involves the reaction of compound-of the formula-(12) with L-Phenylalanine cyClohexylamide of the formula -(13) in NMP at 90°C to yield the compound of the formula -(14), which is treated with CF3SO3H in methanol at 80°C to yield methyl ester of compound of the formula -(15), which is then reacted with BBra to give the compound-of the formula-(16), which on reaction with hydrochloric acid yields Metyrosine of the formula-(1).

Scheme-3:

The general process disClosed in the above publication suffers from several drawbacks espeClally from commerClal point of view. These are (i) the involvement of number of steps (ii) the use of highly toxic chemicals like CF3SO3H, BBra, and (iii) employment of higher temperature. Additional Asymmetric method for the synthesis of Metyrosine is reported in Klaus Weinges et, al., Chem.Ber. 104, 3594-3606 (1971) as shown in Scheme-4.

This approach involves the reaction of 4-Methoxyphenylacetone of the formula -(17) with compound of the formula -(18) and sodium cyanide to yield the compound of the formula -(19), which is further reacted with Raney-Ni followed by sodium hydroxide and hydrochloric acid yields the compound of the formula -(20), which on further reaction with HBr and hydrazine hydrate yields Metyrosine of the formula-(1).
Scheme- 4:

The general process disClosed in the above publication suffers from several drawbacks espeClally from commerClal point of view. These are (i) the use of highly hazardous chemical like Sodium cyanide, (ii) handling of Raney-Ni and (iii) the several steps involved to get pure Metyrosine of the formula-(1). Therefore the process is not an ideal process to be utilized on a commerClal scale.

Additional synthetic method for the synthesis of racemic Metyrosine is reported in K.T.Potts, J.Chem.Soc. 1632-1634 (1955) as shown in Scheme-5. This approach involves the reaction of 4-Methoxyphenylacetone of the formula-(21) with potassium cyanide and ammonium carbonate to yield the compound of the formula-(22), which is further reacted with HI to yield the compound of the formula-(23), which on further hydrolysis with barium hydroxide yields racemic Metyrosine of the formula-(1).
Scheme-5:

In addition the above methods there was a report for the preparation of alpha-alkylation of amino acids by Dieter seebach, Helv.chemica. acta., (1988), 68, 144-154, through imidazolidinones and Nathan k.yee , org.lett. (2000), 2, 2781-2783 Using imidazolidinone derivatives of alpha amino acids but there was no report on preparation of (S)-Methyrosine using this methods. In summary, the processes outlined above for the production of Metyrosine have evident disadvantages inClude.

a), use of highly hazardous chemicals like Sodium cyanide and Potassium
cyanide.
b). expensive reagents are used.
c). handling of toxic chemicals like CF3SO3H, BBra, HI,
d). catalytic hydrogenation steps involved using Raney-Ni and Platinum oxide.
e). longer reaction times.
f). separation of isomers using Si-gel chromatography, which is industrially not
feasible.
g). resolution process requires getting pure Metyrosine.
As such there is a need for effiClent process to produce optically active (-)-
Metyrosine which should avoid Classical resolution, costly raw material,
environmentally safe process, industrially viable asymmetric synthesis which is
cost effective involving inexpensive, readily available, easy to handle reagents.

Objectives of the present invention

Therefore the main objective of the present invention is to provide an improved process for the preparation of Metyrosine of the formula-(1)

over coming the drawbacks of the prior art processes
Another objective of the present invention is to provide an improved process for the preparation of Metyrosine of the formula-(1) avoiding the use of hazardous chemical like Sodium cyanide.

still another objective of the present invention is to provide an improved process
for the preparation of Metyrosine of the formula-(1) avoiding the resolution.
Still another objective of the present invention is to provide an Improved process
for the preparation of Metyrosine of the formula-(1) employing readily available
and easy to handle reagents.
Yet another objective of the present invention is to provide an improved process
for the preparation of Metyrosine of the formula-(1) which can be readily scaled
up to industrial level.
Still another objective of the present invention is to provide an improved process
for the preparation of Metyrosine of the formula-(1), which is simple, convenient,
economical, Eco-friendly and cost effective.
Yet another objective of the present invention is to provide an improved process
for the preparation of Metyrosine of the formula-(1) using novel intermediates of
the formula-(2) and (3).

Formula-(3) Formula-(2)
Wherein R1 to R5= H, CL, Br, and F, R6 = Isobutyl, t-butyl group, R7= Trifluoroacety, acetyl, benzoyl groups and R8= Methyl, ethyl and isopropyl
groups.

Yet another objective of the present invention is to provide novel intermediates of
the formula-(2) & (3) which are useful for the preparation of Metyrosine of the
formula-(1).

Yet another objective of the present invention is to provide a process for the
preparation of novel intermediates of the formula-(2) & (3) which are useful for
the preparation of Metyrosine of the formula-(1).

The above objectives have been achieved by our developing a commerClally
viable asymmetric novel process for preparing Metyrosine of the formula-(1) as
represented from commerClally available cheap raw materials by starting from N-
Boc-L-Alanine as per the Scheme- 6 .

Scheme-6:

Wherein X= Chloride, bromide, iodide, R1 to R5= H, CL, Br, and F,
R6 = Isobutyl, t-butyl group, R7= Trifluoroacety, acetyl, benzoyl groups and R8:
Methyl, ethyl and isopropyl groups.

This is significant that the process of the present invention gives 99.99% chiral purity with chemical purity of >99.6% and further the process does not require any resolution step to remove the unwanted isomer. In addition the process of the present invention employs cheap raw material L-Alanine, which is also easily available commerClally. Furthermore, the process of the present invention provides two novel intermediates of the formula-(2) and the formula-(3)

Formula-(3)
Wherein R1 to R5= H, CL, Br, and F, R6 = Isobutyl, t-butyl group, R7=
Trifluoroacety, acetyl, benzoyl groups and R8= Methyl, ethyl and isopropyl
groups.
The process of the present invention also overcomes the disadvantages of the
prior art processes described above.

• Summary of the Invention:
Accordingly the present invention provides novel compound of the formula-( 2).

Formula-2.
Wherein R1 to R5= H, CL, Br and F; R6= Isobutyl, tert-butyl; R7= trifluoroacetyl, acetyl and benzoyl groups, R8 = Methyl, ethyl and isopropyl groups, which is useful for the preparation of Metyrosine of the formula-(1). According to another embodiment, the present invention provides novel compound of the formula-(3).

Formula-3.
Wherein R1 to R5= H, CL, Br and F, R8= Methyl, ethyl and isopropyl. Which is useful for the preparation of Metyrosine of the formula-(1).

Accordingly the present invention provides an improved process for the preparation of Metyrosine which is (2S)-2-Amino-3-(4-hydroxyphenyl)-2-methyl propanoic acid, of the formula-(1)

Formula-1.
which comprises,
(a), reacting N-Boc-L-alanine of the formula-(24)

Wherein R1 to R5 represent H, CL, Br, and F,
at a temperature in the range from about -50 to 100°C for a period in the range of 13 to 15 hours and in the presence of a base and an organic solvent to provide a compound of the formula-(26)

Wherein R1 to R5 represent the same as defined above, (b). deprotecting the BOC group in the compound of formula-(26) using an acid at a temperature in the range from about -10 to 55°C and for a period in the range from 2 to 20 hours to provide a compound of the formula-(27)

Wherein R1 to R5 represent the same as defined above
(c). cyclising the compound of the formula-(27) with the compound of formula-

Wherein R6 represents iso-butyl or tert-butyl
in an organic solvent at a temperature in the range from about 10 to 100°C and for a
period in the range from 4 to 10 hours to provide compound of the formula-(29).

Wherein R1 to R5 represent the same as defined above, Re represents isobutyl
ortert-butyl.
(d). protecting the amine group of the compound of the formula-(29) with a
suitable amine protecting group in the presence of a base and an organic
solvent at a temperature in the range from about -10 to 40°C and for a duration
in the range from 5 to 6 hours to give a compound of the formula-(30).
H,C.


Wherein R1 to R6 represent the same as defined above and R7 represents an
amine protecting group like trifluoroacetyl, acetyl and benzoyl etc.
(e). reacting the compound of the formula-(30) with a compound of formula-(31)

Wherein R8 represents methyl or ethyl or isopropyl group and X= Chloride, bromide, iodide in the presence of a base and an organic solvent at a temperature in the range from about -50 to 50°C and for a duration in the range from 1 to 6 hours to provide a novel compound of the formula-(2)

Wherein R1 to R7 represent the same as defined above and R8 represents methyl or ethyl or isopropyl
(f). hydrolyzing the novel compound of the formula-(2) using a base followed by an acid in the presence of an organic solvent and the duration of the base hydrolysis ranging from 1 to 10 hours at a temperatures in the range from about 0 to 60°C, the duration of the acidic hydrolysis ranging from 1 to 10 hours and at a ambient temperatures in the range from about 0 to 90°C to provide the novel compound of formula-(3)

R1 to R5 and R8 represent the same as defined above, (g). hydrolyzing followed by demethylation of the compound of the formula-(3) with an acid for a duration in the range from 1 to 30 hours and at a temperature in the range from about 25 to 140°C, to give crude Metyrosine of the formula-
(1)
(h). purifying the crude Metyrosine of the formula-(1) formed in step-(g) using
water and organic solvents like methanol,ethanol, toluene, hepatane, ethyl
acetate, dimethyl formamlde and dimethylsulphoxide and preferably
dimethylformaide and water and most preferably water to provide pure
Metyrosine of theformula-(1).
According to another embodiment of the present invention there is provided a
process for the preparation of novel intermediate of the formula-(2) as defined
above which is useful for the preparation of Metyrosine of the formula-(1) as
defined above which comprises
(a), reacting N-BOC-L-alanine of the formula-(24)

with a compound of formula-(25)

Wherein R1 to R5 represent H, CL, Br, and F,
at a temperature in the range from about -50 to 100°C for a period in the range of 13 to 15 hours and in the presence of a base and an organic solvent to provide a compound of the formula-(26)

Wherein R1 to R5 represent the same as defined above. (b). deprotecting the BOC group in the compound of formula-(26) using an acid at a temperature in the range from about -10 to 55°C and for a period in the range from 2 to 20 hours to provide a compound of the formula-(27)

Wherein R1 to R5 represent the same as defined above
(c). cydising the compound of the formula-(27) with the compound of formula-

(28) Wherein R6 represents iso-butyl or tert-butyl
in an organic solvent at a temperature in the range from about 10 to 100°C and for a period in the range from 4 to 10 hours to provide compound of the formula-(29).

Wherein R1 to R5 represent the same as defined above, R6 represents isobutyl or tert-butyl.
(d). protecting the amine group of the compound of the formula-(29) with a suitable amine protecting group in the presence of a base and an organic
solvent at a temperature in the range from about -10 to 40°C and for a duration in the range from 5 to 6 hours to give a compound of the formula-(30)

Wherein and R1 to R6 represent the same as defined above and R7 represents
an amine protecting group like trifluoroacetyl, acetyl and benzoyl etc.
(e). reacting the compound of the formula-(30) with a compound of formula-(31)

Wherein R8 represents methyl or ethyl or isopropyl group and X= Chloride, bromide, iodide in the presence of a base and an organic solvent at a temperature in the range from about -50 to 50°C and for a duration in the range from 1 to 6 hours to provide a novel compound of the formula-(2)

Wherein R1 to R7 represent the same as defined above and R8 represents
methyl or ethyl or isopropyl
According to yet another embodiment of the present invention there is provided a
process for the preparation of novel intermediate of the formula-(3) as defined
above which Is useful for the preparation of Metyrosine of the formula-(1) as
defined above which comprises.
(a), reacting N-BOC-L-alanine of the formula-(24)

with a compound of formula-(25)

Wherein R1 to R5 represent H, CL, Br, and F,
at a temperature in the range from about -50 to 100°C for a period in the range of 13 to 15 hours and in the presence of a base and an organic solvent to provide a compound of the formula-(26)

Wherein R1 to R5 represent the same as defined above, (b). deprotecting the BOC group in the compound of formula-(26) using an acid at a temperature in the range from about -10 to 55°C and for a period in the range from 2 to 20 hours to provide a compound of the formula-(27)

Wherein R1 to R5 represent the same as defined above
(c). cyclising the compound of the formula-(27) with the compound of formula-

Wherein R6 represents isobutyl or tert-butyl
in an organic solvent at a temperature in the range from about 10 to 100°C and for a
period in the range from 4 to 10 hours to provide compound of the formula-(29).

Wherein R1 to R5 represent the same as defined above, R6 represents isobutyl or tert-butyl.

(d). protecting the amine group of the compound of the formula-(29) with a suitable amine protecting group in the presence of a base and an organic solvent at a temperature in the range from about -10 to 40°C and for a duration in the range from 5 to 6 hours to give a compound of the formula-(30)

wherein R1 to R6 represent the same as defined above and R7 represents an
amine protecting group like trifluoroacetyl, acetyl and benzoyl etc.
(e). reacting the compound of the formula-(30) with a compound of formula-(31)

Wherein R8 represents methyl or ethyl or isopropyl group and X= Chloride, bromide, iodide in the presence of a base and an organic solvent at a temperature in the range from about -50 to 50°C and for a duration in the range from 1 to 6 hours to provide a novel compound of the formula-(2)

Wherein R1 to R7 represent the same as defined above and R8 represents methyl or ethyl or isopropyl
(f). hydrolyzing the novel compound of the formula-(2) using a base followed by an acid in the presence of an organic solvent and the duration of the base hydrolysis ranging from 1 to 10 hours at a temperatures in the range from about 0 to 60 C, the duration of the acidic hydrolysis ranging from 1 to 10 hours and at a ambient temperatures in the range from about 0 to 90°C to provide the novel compound of formula-(3)

R1 to R5 and R8 represent the same as defined above.

Detailed Description of the Invention:
In the step-(a) N-Boc-L-Alanine of the formula-(24) is reacted with compound of formula-(25) wherein preferably R1,R2, R4,R5 represent hydrogen and R3 represents halogen, more preferably R1,R5 represent s hydrogen and R2, R3,R4 represent halogen and still more preferably R1,R3,R5 represent hydrogen and R2,R4 represent halogen in the presence of Isobutylchloroformate more preferably Ethylchloroformate and organic base to provide the compound of formula-(26)

The reaction is carried out in organic solvents such as toluene, THF, dichloromethane, ethylene dichloride, chloroform more preferably dichloromethane in the presence of organic base and most preferable base is N-MethylmorJDholine at a temperature preferably in the range - 35 to 5°C. The duration of the reaction may preferably in the range from 12 to 14 hours.

In the step-(b) of the reaction, the compound of the formula-(26) is treated with acids in organic solvent to get the compound of the formula-(27) the acid used in the reaction can be selected from group consisting of hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, trifluoroacetic acid, methane sulfonicacid, benzene sulfonicacid, phosphoric acid, p-toluenesulfonic acid and preferably hydrochloric acid. The amount of acid used in the reaction may be in the range of 1-10 molar equivalents and preferably using 7-9 molar equivalents. The solvent used for the reaction selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile and preferably using methanol. The reaction temperature may preferably in the range from 15 to 30°C. The duration of the reaction may preferably range from 15 to 18 hours.

In the step-(c) of the reaction, the compound of formula-(27) is treated with compound of formula-(28) wherein R6 represents tert- butyl more preferably isobutyl in a organic solvent to provide compound of formula-(29) The reaction is carried out in organic solvents such as toluene, THF, MTBE, pentane, hexane, heptane more preferably toluene at ambient temperatures in the range preferably from about 45 to 55°C and the duration of the reaction may preferably in the range from 6 to 8 hours.
In the step-(d) of the reaction, amine group of the compound of the formula-(29) is protected with suitable amine protecting groups more preferably group is trifluoroacetyl in the presence of organic base in a organic solvent to provide compound of formula-(30)
The base used in the reaction can be selected from group consisting of imidazole, lutidine, pyridine, DIPEA, triethylamine and preferably triethylamine. The amount of base used in the reaction may be in the range of 1-5 molar equivalents and preferably using 1-2 molar equivalents. The solvent used for the reaction selected from ether solvents such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, dimethylformamide, chlorinated solvents such as methylene chloride, ethylene dichloride, chloroform and preferably using dichloromethane. The reaction temperature may preferably range from about -5 to 5°C. The duration of the reaction may preferably range from 2 to 3 hours. In the step-(e) of the reaction, compound of the formula-(30) is reacted with compound of the formula-(31) wherein R8 represents methyl ,ethyl and isopropyl more preferably methyl in the presence of organic base in a organic solvent to provide the novel compound of formula-(2).
The base used in the reaction can be selected from group consisting of potassium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium hydride, LDA, potassium hydroxide, sodium hydroxide. Sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and preferably lithium bis(trimethylsilyl)amide. The amount of base used in the reaction may be in the range of 1-3 molar equivalents and preferably using 1-2 molar equivalents. The solvent used for the reaction selected from ether solvents such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, dimethylformamide, hydrocarbon solvents such as toluene, xylene, hexane, cyClohexane and preferably using tetrahydrofuran. The reaction temperature may preferably range from about -30 to 0°C. The duration of the reaction may preferably range from 2 to 3 hours.

In the step-(f) of the reaction, compound of the formula-(2) is hydrolyzed with
base followed by acid in organic solvent to provide the novel compound of the

formula-(3).
The base used in the reaction can be selected from group consisting of sodium
hydroxide, potassium hydroxide, lithium hydroxide, triton-B and preferably
potassium hydroxide. The acid used in the reaction can be selected from group
consisting of hydrochloric acid, hydrogen bromide, sulfuric acid and preferably
sulfuric acid. The solvent used for the reaction selected from ether solvents such
as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, dimethylformamide,
alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol
and preferably using isopropyl alcohol. The duration for basic hydrolysis of the
reaction may preferably range from 2 to 4 hours at a temperature preferably in
the range from about 40-50°C. The duration for acidic hydrolysis of the reaction
may preferably range from 1 to 3 hours at a temperature in the range from about
60-75°C.

In the step-(g) of the reaction, the novel compound of the formula-(3) is
hydrolyzed followed by demethylation with acid to provide Metyrosine of the
formula-(1).
The acid used in the reaction can be selected from group consisting of
hydrochloric acid, hydrogen bromide, sulfuric acid, BBrs and preferably hydrogen
bromide. The duration of the reaction may preferably range from 20 to 24 hours
at a temperature preferably in the range from about 115-130°C.

In the step-(h) of the reaction Metyrosine compound of formula-(1) formed in
step-(g) is purified using water and organic solvents like methanol, ethanol,
isopropanol, ethylacetate, toluene, heptane.dimethylformamide, and
dimethylsulfoxide and mixture thereof to provide pure Metyrosine compound of
formula-(1).

This invention provides an effiClent method for the production of (S)-Metyrosine
with chiral purity of >99.9%.
The details of the invention are given in the examples provided below, which are given
to illustrate the invention only and therefore should not be construed to limit the scope
of the invention.

EXAMPLE-1: Step- (a): Preparation of (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester(32).

Dissolved N-BOC-L-Alanine (200 gm, 1.057 mol) in methylene chloride (800 ml) under stirring. Cooled the resulting reaction mixture to -15 to -10°C, added N-methyl morpholine (128.3 gm, 1.268 mol) then further cooled to -35°C, added ethylchloroformate (131.9 gm, 1.215 mol) followed by 3,5-dichloroaniline (171.2 gm, 1.057 mol). Stirred the above reaction mixture at 0 to 5°C for a period of 16-18 hours. Quenched the reaction mixture with water (500 ml), stirred for 10-15 minutes and separated the organic layer. The organic layer was washed with water (2x200 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, added hexane (400 ml) and stirred for 30 minutes at 0-5°C. Filtered the resulting solid and washed with hexane (100ml). Dried until constant weight is reached. Dry weight of obtained (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester is 300.0 gm. Yield: 85.1%;

Melting point of the resulting compounds ranges from 138.1-140.5°C; IR spectra (cm'^): 3321, 2981, 1671, 1589, 1539,1446, 1317, 1255, 1165, 1117, 1072,858,802;
H NMR (400 MHz, CDCL3): 69.27(br.s, 1H), 7.37(s, 2H), 6.96(s, 1H), 5.42 (br.d,
J=5.16Hz, 1H), 4.39(br.s, 1H),1.47 (s, 9H), 1.41(d, J=7.00Hz. 3H).
Mass (m/z): 334.2 [M+Hf.

Step- (b): Preparation of (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide
(33).

Dissolved (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (200.0 gm, 0.599 mol) obtained from step-(a) in methanol (300 ml). To the resulting mixture Cone, hydrochloric acid (500 ml) and water (320 ml) are added at 20-25°C. The resulting reaction mixture was stirred for 16-18 hours at 20-25°C. Added water (200 ml) and toluene (400 ml), cooled to 5-10°C, then basified with 50% sodium hydroxide solution. Stirred for 15 minutes and separated the layers. Aqueous layer was washed with toluene (3x200ml). Combined organic layers and washed with water, dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure to get the title compound as brown colored syrup.

Weight: 135.0 gm.
Yield: 96.4%;
IR spectra (cm'^): 3281, 2969, 2930, 1681, 1585, 1515, 1445, 1409, 1372, 1258, 1185,1112,925,843,798,669;
1H NMR (400 MHz, CDCL3) : 59.67(br.s, 1H), 7.50(s, 2H), 7.00(s, 1H), 3.51 (q,
J=7.03Hz, 1H), 1.65(br.s, 2H),1.34(d, J=7.04Hz, 3H).
Mass (m/z): 234.09 [M+H]^
Step- (c): Preparation of (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-
imiClazolidin-4-one(34).

Dissolved (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide (135 gm, 0.579 mol)
obtained in step-(b) in toluene (925 ml) under stirring. Cooled the resulting reaction
mixture to 20°C, added isobutyraldehyde (83.5 gm, 1.157mol) over a period of 50 to 60
minutes. Stirred the above reaction mass at 50 to 55°C for a period of 18-19 hours. The
organic layer was distilled off under reduced pressure, added hexane (270 ml) and
stirred for 1.45 hours at 0-5°C. Filtered the resulting solid and washed with hexane
(50ml). Dried until constant weight is reached. Dry weight of obtained (S)- 3-(3,5-
Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one is 138.0 gm.
Yield: 82.98%;

Melting point ranges from 128.9-131.8°C;
IR spectra (cm"^): 3305, 3051, 2962, 2877, 1689, 1587, 1450, 1383, 1278, 1223,
1055,846,798,743;
1H NMR (400 MHz, CDCL3) : 57.40 (s, 2H), 7.15 (s, 1H), 5.00 (s, 1H), 3.68 (q,
J=6.83Hz, 1H), 1.98 (br.s, 1H), 1.35 (d, J=6.84Hz, 3H), 0.96(d, J=6.87Hz, 3H),
0.76 (d, J=6.70Hz, 3H).
Mass (m/z): 288.1 [M+Hf.

Step- (d): Preparation of (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-
methyl-1 -(2,2,2-trifluoroacetyl)-imidazolidin-4-one (35).

Dissolved (S)-3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one (135 gm, 0.470 mol) obtained in step-(c) in methylene chloride (1080 ml) under stirring. Cooled the resulting reaction mixture to 0 to 5°C, added triethyl amine (66.48 gm, 0.658 mol) followed by trifluoroacetlc anhydride (132.3 gm, 0.658 mol) over a period of 30 minutes. Stirred the above reaction mass at 0 to 5°C for a period of 2-3 hours. Quenched the reaction mixture with water (405 ml), stirred for 20-25 minutes and separated the organic layer. The organic layer was washed with water (2x270 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, to get crude product as semi solid. The obtained semi solid mass was recrystalised using isopropyl alcohol to get pure product. Dried until constant weight is reached. Dry weight of obtained (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one is 153.0 gm.

Yield: 84.93%;

Melting point ranges from 96.8-98.6°C;
IR spectra (cm-""): 2975, 1725, 1682, 1586, 1574, 1435, 1200, 1164, 931, 802;
^H NMR (400 MHz, CDCL3) : 57.46 (s, 2H), 7.26 (s, 1H), 6.18 (s, 1H), 4.55 (q,
J=6.52Hz, 1H), 1.73 (d, J=7.04Hz, 3H), 0.94 (d, J=7.20Hz, 3H), 0.73 (d, J=7.08Hz,
3H).

Mass (m/z): 384.1 [M+Hf.

Step- (e): Preparation of (2S, 5S)-2-i8opropyl-3-(3,5-Dichloro-phenyl)-5-
methyl-1-(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imiClazolidin-4-one(36).

Dissolved the (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one (100 gm, 0.260 mol) obtained in step-(d) in tetrahydrofuran (500 ml) under stirring. Added 4-Methoxybenzyl bromide (63.0 gm, 0.313 mol) in one portion. Cooled the resulting reaction mixture to -5°C, added lithium bis(trimethylsilyl)amide solution in tetrhydrofuran (240.5 gm, 0.287 mol) over a period of 1 hour 30 minutes by keeping temperature at -5 to 0°C. Stirred the above reaction mass for a period of 2-3 hours at same temperature. Added 5% ammonium chloride solution (300 ml), and ethyl acetate (300ml), stirred for 20-25 minutes and separated the organic layer. Aqueous layer extracted with ethyl acetate (300 ml). Combined the
organic layers and washed with saturated sodium chloride solution (300ml), dried with
anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced
pressure, added isopropyl alcohol (100 ml) and stirred for 30 minutes at 0-5°C. Filtered
the resulting solid and washed with isopropyl alcohol (25ml). Dried until constant weight
is reached. Dry weight of obtained (2S, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-
methyl-1-(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one is 104.0 gm.

Yield: 79.20%;
Melting point ranges from 140.5-142.8°C;
IR spectra (cm2): 2970, 1727, 1692, 1611, 1584, 1570, 1512, 1452, 1346, 1252,
1164, 1038,847,732;
^H NMR (400 MHz, DMSO-de) : 57.56 (s,1H), 7.20(s, 2H), 6.77(d, J=8.5Hz, 2H),
6.69(d, J=8.5Hz, 2H), 5.49(s, 1H), 3.72(s, 3H). 3.50(d, J=13.8Hz, 1H). 2.88(d,
J=13.8Hz, 1H), 1.93(t, J=6.84Hz, 1H), 1.82(s, 3H), 0.83(d, J=6.61Hz, 3H), 0.47(d,
J=7.21Hz, 3H).
Mass (m/z): 504.3 [M+H]*.

Step- (f): Preparation of (S)-2-amino-N-(3,5-Dlchloro-phenyl)-2-methyl-3-(4-
methoxy phenyi)-propionamide (37).

To the suspension of potassium hydroxide (22.96 gm, 0.349 mol) in isopropyl alcohol (400 ml), (2S, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one (100 gm, 0.198 mol) obtained in step-(e) was added at 25 to 30°C under stirring. The resulting reaction mixture was stirred at 40 to 45°C for 3-4 hours. Cooled to 10 to 15°C,added 3M sulfuric acid (300 ml) over a period of 30 minutes. The resulting reaction mixture was heated to 70 to 75°C, stirred for 2 to 3 hours at same temperature. Distilled solvent completely under reduced pressure, added water (500 ml) and ethyl acetate (500 ml). Stirred for 15 minutes and basified with 20% sodium hydroxide solution. Stirred for 15 minutes at 25 to 30°C, separated the organic layer. Aqueous layer washed with ethyl acetate (500 ml). Combined the organic layers and washed with saturated sodium chloride solution (250 ml), dried over anhydrous sodium sulfate, filtered. Removed solvent completely under reduced pressure to get the title compound as brown colored syrup. Weight of (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-methoxy phenyl)-propionamide is 59.8 gm.

Yield: 85.2%;
IR spectra (cm"^): 2960, 2836, 1682, 1575, 1514, 1446, 1407, 1249, 1179. 1115, 1037,845,803;
^H NMR (400 MHz, CDCL3) : 59.82(br.s, 1H), 7.52(s, 2H), 7.06(d, J=8.27Hz, 3H), 6.79(d, J=8.28Hz, 2H), 3.75(s, 3H), 3.37(d. J=13.53Hz, 1H), 2.58(d, J=13.54Hz, 1H), 2.12(br.s, 2H), 1.42(s, 3H). Mass (m/z): 354.2 [M+Hf-

Step- (g): Preparation of (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (1) (IVietyrosine).
Dissolved the (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-methoxy phenyl)-
propionamide (70 gm, 0.98 mol) obtained in step-(f) in aqueous HBr (840 ml) under
stirring. The resulting reaction mixture was heated to 120-125°C and stirred for 24
hours. Cooled to 50°C, added water (2100 ml) stirred for 15 minutes then further cooled
to 10-15°C , pH adjusted to 5-6 with ammonium hydroxide solution. Stirred for 30
minutes at 10-15°C, filtered and cake washed with water (2x200 ml). Dried until
constant weight is reached.
Dry weight of obtained crude (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic
acid (Metyrosine) of formula-1 is 52.0 gm.
Step- (h): Purification of (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic
acid (1) (l\/letyrosine).
The crude (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine)
obtained in step ( g) 10.0 gm) was dissolved in water (1000 ml) by heating the reaction
mixture to 90°C. Darco (Charcoal) was added and stirred for 10-15 minutes at same
temperature. The resulting reaction mixture was filtered through celite bed. The filtered
reaction mass concentrated up to half volume reached under reduced pressure. Cooled
to 10°C and stirred for a period of 30 minutes at same temperature. Filtered the
resulting solid, washed with water. Dried until constant weight is reached.

Dry weight of obtained pure (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic
acid (Metyrosine) of formula-1 was 3.6 gm.
Purity: 99.69%.

Chiral purity by HPLC: 100.0%.
IR spectra (cm'^): 3416, 3251. 1636,1577, 1515, 1450, 1403, 1369, 1267, 1242,
1126,1057,1032,831,770;
^H NMR (400 MHz, D2O) : 56.79 (d, J=8.49Hz, 2H), 6.52 (d, J=8.48H2, 2H), 2.93 (d,
J=14.52Hz, 1H), 2.68 (d, J=14.54Hz, 1H), 1.29 (s, 3H).
Mass(m/z): 196.2 [M+Hf.
^^C NMR (400 MHz, D2O): 5172.6, 154.5, 130.9, 124.0, 115.2, 60.2, 40.7, 20.8.

EXAMPLE-2 Step- (a): Preparation of (S)-[1-(4-Fluoro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (38).

Dissolved N-BOC-L-Alanine (50 gm, 0.264 mol) in methylene chloride (200 ml) under stirring. Cooled the resulting reaction mixture to -15 to -10°C. N-methyl morpholine (32.10 gm, 0.317 mol) was added and then further cooled to -35°C, Ethylchloroformate (32.97 gm, 0.303 mol) was added followed by 4-fluoroaniline (29.3 gm, 0.264 mol). Stirred the above reaction mixture at 0 to 5°C for a period of 16-18 hours. Quenched the reaction mixture with water (125 ml), stirred for 10-15 minutes and separated the organic layer. The organic layer was washed with water (2x75 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, added hexane (100 ml) and stirred for 30 minutes at 0-5°C. Filtered the resulting solid
and washed with hexane (50ml). Dried until constant weight is reached. Dry weight of
obtained (S)-[1-(4-Fluoro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester is 68.0
gm.

Yield: 91.10%.
Melting point ranges from 140.5-144.5°C;
IR spectra (cm'^): 3352, 3335, 2924,1676, 1535,1512, 1406,1318, 1156, 830;
^H NMR (400 MHz, CDCL3) : 58.93(br.s, 1H), 7.40(d, J=4.52Hz, 2H), 6.89(s, 2H),
5.42(d, J=7.12Hz, 1H), 4.41(br.s, 1H), 1.44(s, 12H).
Mass (m/z): 283. [M+H]*.

Step- (b): Preparation of (S)- 2-Amino-N-(4-fluoro-phenyl)-propionamide
(39).

Dissolved (S)-[1-(4-Fluoro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (60.0 gm, 0.212 mol) obtained form step-(a) in methanol (300 ml) is added to a mixture of Cone, hydrochloric acid (176.3 ml, 1.594 mol) and water (96 ml) at 20-25°C. The resulting reaction mixture was stirred for 16-18 hours at 20-25°C. Added water (120 ml) and toluene (180 ml), cooled to 5-10°C, then basified with 50% sodium hydroxide solution. Stirred for 15 minutes and separated the layers. Aqueous layer was washed with toluene (2x180ml). Combined organic layers and washed with water, dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure to get the title compound
as brown colored syrup. Weight: 34.6 gm,

Yield: 89.40%;
IR spectra (cm^^): 3292, 2974, 1673, 1614, 1511, 1408, 1305, 1212, 1068, 949,
832;
^H NMR (400 MHz, CDCL3) : 59.49(br.s, 1H), 7.52(dd, J=2.11Hz, 2H), 6.95(t,
J=8.58, 6.73H2, 2H), 3.54(q, J=6.95, 7.0, 6.97H2, 1H), 1.77(br.s, 1H), 1.35(d,
J=5.82Hz, 3H).
Mass (m/z): 183.3 [M+H^.
Step- (c): Preparation of (S)- 3-(4-fluoro-phenyl)-2-isopropyi-5-methyl-
imidazolidin-4-one (40).

Dissolved the (S)- 2-Amino-N-(4-fluoro-phenyl)-propionamide (31 gm, 0.170 mol) obtained in step-(b) in toluene (221 ml) under stirring. Cooled the resulting reaction mixture to 20°C, added isobutyraldehyde (24.5 gm, 0.340mol) over a period of 50 to 60 minutes. Stirred the above reaction mass at 50 to 55°C for a period of 18-19 hours. The organic layer was distilled off under reduced pressure, to get the title compound as brown colored syrup. Weight: 38 gm, Yield: 94.50%; IR spectra (cm"^): 2968, 2875, 1694,1602, 1510, 1401, 1337, 1232, 1096, 832;
1H NMR (400 MH^, CDCL3) : 67.34(dd, J=4.02Hz, 1H), 7.20(dd, J=3.93Hz, 1H),
7.04(t, J=8.34, 8.70Hz, 2H), 4.99(s, 1H), 3.65(q, J=6.84Hz. 1H), 1.23(q, J=9.8Hz,
1H), 0.93(d, J=6.97Hz, 3H), 0.85(d, J=6.35Hz, 3H), 0.77(d, J=6.72Hz, 3H).
Mass (m/z): 237.2 [M+Hf.
Step- (d): Preparation of (2R, 5S)-2-isopropyl-3-(4-fluoro-phenyl)-5-methyl-
1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one(41).

Dissolved the (S)- 3-(4-fluoro -phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one (30 gm, 0.126 mol) obtained in step-(c) in methylene chloride (240 ml) under stirring. Cooled the resulting reaction mixture to 0 to 5°C, added triethyl amine (15.37 gm, 0.151 mol) followed by trifluoroacetic anhydride (30.5 gm, 0.151 mol) over a period of 30 minutes. Stirred the above reaction mass at 0 to 5°C for a period of 2-3 hours. Quenched the reaction mixture with water (90 ml), stirred for 20-25 minutes and separated the organic layer. The organic layer was washed with water (2x90 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, to get crude product as semi solid. The obtained semi solid mass was recrystalised using isopropyl alcohol, heptane to get pure product. Dried until constant weight is reached. Dry weight of obtained (2R,5S)-2-isopropyl-3-(4-fluoro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one is 16.8 gm.

Yield: 39.85%;
Melting point ranges from 82.8-87.2°C;
IR spectra (cm"^): 2977, 1702. 1685, 1519, 1465, 1343, 1254, 1218, 1160, 832;
^H NMR (400 MHz, CDCL3): 67.42(dd, J=4.08Hz, 2H), 7.12(t, J=8.44, 8.56H2. 2H),
6.13(s, 1H), 4.55(q, J=6.52H2, 1H), 2.38(q, J=6.84Hz, 1H), 1.68(d, J=6.36Hz, 3H),
0.89(d, J=6.80, 3H), 0.66(d, J=7.16, 3H).
Mass (m/z): 333.3 [M+Hf.
Step- (e): Preparation of (2S, 5S)-2-i8opropyl-3-(4-fluoro-phenyl)-5-methyl-1-
(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one(42).
OMe

Dissolved (2R, 5S)-2-isopropyl-3-(4-fluoro-phenyl)-5-methyl-1 -(2,2,2-trifluoroacetyl)-imidazolidin-4-one (5 gm, 0.015 mol) obtained in step-(d) in tetrahydrofuran (25 ml) under stirring. Added 4-Methoxybenzyl bromide (3.6 gm, 0.017 mol) in one portion. Cooled the resulting reaction mixture to -30°C, added lithium bis(trimethylsilyl)amide solution in tetrhydrofuran (28 gm, 0.033 mol) over a period of 1 hour 30 minutes by keeping temperature at -30 to -25°C. Stirred the above reaction mass for a period of 2-3 hours at same temperature. Added 5% ammonium chloride solution (30 ml), and ethyl acetate (30ml), stirred for 20-25 minutes and separated the organic layer. Aqueous layer extracted with ethyl acetate (30 ml). Combined the organic layers and washed with
saturated sodium chloride solution (30ml), dried with anhydrous sodium sulfate and
filtered. The organic layer was distilled off under reduced pressure, added isopropyl
alcohol (5 ml) and heptane (20 ml) stirred for 30 minutes at 0-5°C. Filtered the resulting
solid and washed with heptane (10ml). Dried until constant weight is reached. Dry
weight of obtained (2S, 5S)-2-isopropyl-3-(4-fluoro-phenyl)-5-methyl-1-(2,2,2-
trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one is 5.8 gm.
Yield: 85.2%;
Melting point ranges from 102.4-105.2°C;
IR spectra (cm"^): 2984, 1714. 1691,1611, 1513, 1428, 1349, 1216, 1031, 850;
^H NMR (400 MHz, CDCL3) : 7.22(t, J=8.76,8.68Hz, 2H), 7.08(dd, J=4.00Hz, 2H),
6.80(d, J=8.60Hz, 2H), 6.73(d, 8.59Hz, 2H), 5.26(s, 1H), 3.75(s, 3H). 3.48(d,
J=13.84Hz, 1H), 2.94(d, J=13.81Hz, 1H), 1.90(q, J=6.94Hz, 1H), 1.80(s, 3H),
0.85(d, J=6.65Hz, 3H), 0.39(d, J=7.28Hz, 3H).
Mass (m/z): 453.4 [M+Hf.

Step- (f): Preparation of (S)-2-amlno-N-(4-fluoro-phenyl)-2-methyl-3-(4-methoxy
phenyl)-propionamide(43).

To the suspension of potassium hydroxide (1.30 gm, 0.023 mo!) in isopropyl alcohol (20 ml) was added (2S, 5S)-2-isopropyl-3-(4-fluoro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one (5 gm, 0.011 mol) obtained in
step-(e) at 25 to 30°C under stirring. The resulting reaction mixture was stirred at 40 to 45°C for 3-4 hours. Cooled to 10 to 15°C,added 3M sulfuric acid (15 ml) over a period of 30 minutes. The resulting reaction mixture was heated to 70 to 75°C, stirred for 2 to 3 hours at same temperature. Distilled solvent completely under reduced pressure, added water (25 ml) and ethyl acetate (50 ml). Stirred for 15 minutes and basified with 20% sodium hydroxide solution. Stirred for 15 minutes at 25 to 30°C, separated the organic layer. Aqueous layer washed with ethyl acetate (25 ml). Combine the organic layers and washed with saturate sodium chloride solution (25 ml), dried over anhydrous sodium sulfate, filtered. Removed solvent completely under reduced pressure to get the title compound as brown colored syrup. Weight of (S)-2-amino-N-(4-fluoro-phenyl)-2-methyl-3-(4-methoxy phenyl)-propionamide is 4.0 gm, which is directly used for next stage. IR spectra (cm'^): 2923, 1671, 1611,1510, 1405, 1302, 1246, 1028, 825; ^H NIVIR (400 MHz, CDCL3) : 89.64(br.s, 1H), 7.47(dd, 2.03Hz, 2H), 7.09(d, J=8.47H2, 2H), 6.95(t, J=8.63,8.70Hz, 2H), 6.79(d, J=8.51H2. 2H), 3.73(s, 3H), 3.39(d, J=13.50Hz, 1H), 2.58(d, J=13.52Hz, 1H), 1.65(br.s, 2H), 1.43(s, 3H). Mass (m/z): 303.4 [M+Hf.
Step- (g): Preparation of (2S)-2-amino-3-(4-hydroxyphenyl)-2-methyi propanoic acid (1) (IMetyrosine).

Dissolved-(S)-2-amino-N-(4-fluoro-phenyl)-2-methyl-3-(4-methoxyphenyl)-propionamide (4 gm) obtained in step-(f) in aqueous HBr (50 ml) under stirring. The resulting reaction mixture was heated to 120-125°C and stirred for 24 hours. Cooled to 50°C, added water (100 ml) stirred for 15 minutes then further cooled to 10-15°C, pH adjusted to 5-6 with ammonium hydroxide solution. Stirred for 30 minutes at 10-15°C, filtered and cake washed with water (2x200 ml). Dried until constant weight is reached. Dry weight of obtained crude (2S)-2-amino-3-(4-hydroxyphenyl)-2-methyl propanoic acid (Metyrosine) is2.0gm.
Step- (h): Purification of (2S)-2-amino-3-(4-hydroxyphenyl)-2-metliyl propanoic acid (IVIetyrosine).
The crude (2S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid(Metyrosine) obtained in step ( g) (2.0 gm) was dissolved in water (200 ml) by heating the reaction mixture to 90°C. Darco was added and stirred for 10-15 minutes at same temperature. The resulting reaction mixture was filtered through celite bed. The filtered reaction mass concentrated up to half volume reached under reduced pressure. Cooled to 10°C and stirred for a period of 30 minutes at same temperature. Filtered the resulting solid, washed with water. Dried until constant weight is reached. Dry weight of obtained pure (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine) of formula-1 is 0.8 gm. The product is matching in all respects with compounds of Metyrosine obtained from Example-1 (step-h). Purity: 99.70% by HPLC. Chiral purity by HPLC: 100.0%.

EXAMPLE-3. Step- (a): Preparation of (S)- [1-(3,5-DiCliloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester(32).
Dissolved N-BOC-L-Alanine (100 gm, 0.528 mol) in methylene chloride (400 ml) under stirring. Cooled the resulting reaction mixture to -15 to -10°C, added N-methyl morpholine (64.15 gm, 0.634 mol) then further cooled to -35°C, added
ethylchloroformate (66 gm, 0.667 mol) followed by 3,5-dichloroaniline (85.62 gm, 0.528 mol). Stirred the above reaction mixture at 0 to 5°C for a period of 16-18 hours. Quenched the reaction mixture with water (250 ml), stirred for 10-15 minutes and separated the organic layer. The organic layer was washed with water (2x100 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, added hexane (200 ml) and stirred for 30 minutes at 0-5°C. Filtered the resulting solid and washed with hexane (50ml). Dried until constant weight is reached. Dry weight of obtained (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester is 156.0 gm. Yield: 88.5%;

Step- (b): Preparation of (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide (33).

Dissolved (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (150.0 gm, 0.450 mol) obtained from step-(a)) in methanol (265 ml) To the resulting mixture Cone, hydrochloric acid (375 ml) and water (240 ml) are added at 20-25°C. The resulting reaction mixture was stirred for 16-18 hours at 20-25°C. Added water (150 ml) and toluene (300 ml), cooled to 5-10°C, then basified with 50% sodium hydroxide solution. Stirred for 15 minutes and separated the layers. Aqueous layer was washed with toluene (3x150ml). Combined organic layers and washed with water, dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure to get the title compound as brown colored syrup. Weight: 104.0 gm.

Yield: 99.1%;
Step- (c): Preparation of (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyi-imidazolidin-4-one (34).

Dissolved (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide (104 gm, 0.446 mol) obtained in step-(b) in toluene (715 ml) under stirring. Cooled the resulting reaction mixture to 20°C, added isobutyraldehyde (64.34 gm, 0.892mol) over a period of 50 to 60 minutes. Stirred the above reaction mass at 50 to 55°C for a period of 18-19 hours. The organic layer was distilled off under reduced pressure, added hexane (200 ml) and stirred for 3 hours at 0-5°C. Filtered the resulting solid and washed with hexane (25ml). Dried until constant weight is reached. Dry weight of obtained (8)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one is 101.0 gm. Yield: 78.90%; Step- (d): Preparation of (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyi-1 -(2,2,2-trifIuoroacetyl)-imidazo[idin-4-one (35).

Dissolved (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one (100 gm, 0.348 mol) obtained in step-(c) in methylene chloride (800 ml) under stirring. Cooled the resulting reaction mixture to 0 to 5°C, added triethyl amine (42.28 gm, 0.417 mol) followed by trifluoroacetic anhydride (87.73 gm, 0.417 mol) over a period of 30 minutes. Stirred the above reaction mass at 0 to 5°C for a period of 2-3 hours. Quenched the reaction mixture with water (300 ml), stirred for 20-25 minutes and separated the organic layer. The organic layer was washed with water (2x200 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, to get crude product as semi solid. The obtained semi solid mass was recrystalised using isopropyl alcohol to get pure product. Dried until constant weight is reached. Dry weight of obtained (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one is 94.0 gm. Yield: 70.67%; Step- (e): Preparation of (2S, 5S)-2-isopropyl-3-(3,5-Dichioro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-5-(4-ethoxybenzyl)-imidazolidin-4-one(44).
OCjHj

Dissolved the (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one (8 gm, 0.0208 mol) obtained in step-(d) in tetrahydrofuran (40 ml) under stirring. Added 4-Ethoxybenzyl bromide (5.45 gm, 0.025 mol) in one portion. Cooled the resulting reaction mixture to -5°C, added lithium bis(trimethylsilyl)amide solution in tetrhydrofuran (12.2 gm, 0.0229 mol) over a period of 1 hour 30 minutes by keeping temperature at -5 to 0°C. Stirred the above reaction mass for a period of 2-3 hours at same temperature. Added 5% ammonium chloride solution (40 ml), and ethyl acetate (40ml), stirred for 20-25 minutes and separated the organic layer. Aqueous layer extracted with ethyl acetate (40 ml). Combined the organic layers and washed with saturated sodium chloride solution (40ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, added isopropyl alcohol (100 ml) and stirred for 30 minutes at 0-5°C. Filtered the resulting solid and washed with isopropyl alcohol (25ml). Dried until constant weight is reached. Dry weight of obtained (2S, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-
1-(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one is 6.6 gm.
Yield: 61.10%;

Melting point ranges from 114.2-116.4°C;
IR spectra (cm'^): 2977, 1731, 1692, 1609, 1585, 1572. 1513, 1426, 1348, 1250,
1197, 1048,890,748;
^H NMR (400 MHz, CDCL3) : 57.29 (s,1H), 6.84(d, J=8.5Hz, 2H), 6.80(d, J=1.5H2,
2H), 6.73(d, J=8.1Hz, 2H), 5.07(s, 1H), 3.99(q, J=6.9Hz, 2H), 3.66(d, J=13.8Hz,
1H), 2.99(d, J=13.8Hz, 1H), 2.05(t, J=6.94Hz, 1H), 1.95(s, 3H), 1.41(t, J=6.94Hz,
3H), 0.91 (d, J=6.61Hz, 3H), 0.52(d, J=7.30Hz, 3H).
Mass (m/z): 517.3 [M+Hf.
Step- (f): Preparation of (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-ethoxy
phenyl)-propionamlde (45).

To the suspension of potassium hydroxide (1.12 gm, 0.0169 mol) in isopropyl alcohol (25 ml) , (2S, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-5-(4-ethoxy benzyl)-imidazolidin-4-one (5.0 gm, 0.009 mol) obtained in step-(e) was added at 25 to 30°C under stirring. The resulting reaction mixture was stirred at 40 to
45°C for 3-4 hours. Cooled to 10 to 15°C,added 3M sulfuric acid (15 ml) over a period of 30 minutes. The resulting reaction mixture was heated to 70 to 75°C, stirred for 2 to 3 hours at same temperature. Distilled solvent completely under reduced pressure, added water (25 ml) and ethyl acetate (50 ml). Stirred for 15 minutes and basified with 20% sodium hydroxide solution. Stirred for 15 minutes at 25 to 30°C, separated the organic layer. Aqueous layer washed with ethyl acetate (50 ml). Combined the organic layers and washed with saturate sodium chloride solution (25 ml), dried over anhydrous sodium sulfate, filtered. Removed solvent completely under reduced pressure to get the title compound as brown colored syrup. Weight of (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-ethoxy phenyl)-propionamide is 2.8 gm. Yield: 79.0%;
IR spectra (cm"^): 2981, 1732, 1689, 1682, 1575, 1513, 1446, 1302, 1244, 1179, 1116, 1048, 843;
^H NMR (400 MHz, CDCL3) : 59.79(br.s, 1H), 7.52(s, 2H), 7.05(d, J=8.68Hz, 3H), 6.79(d, J=8.53Hz, 2H), 3.94(q, J=6.98, 2H), 3.38(d, J=13.25Hz, 1H), 2.57(d, J=13.56Hz, 1H), 2.03(s, 1H), 1.58(br.s, 2H), 1.43(s, 3H),1.39(t, J=5.42Hz, 3H), Mass (m/z): 368.2 [M+Hf.

Step- (g): Preparation of (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine).
Dissolved the (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-ethoxy phenyl)-propionamide (2.8 gm, 0.007 mol) obtained in step-(f) in aqueous HBr (50 ml) under stirring. The resulting reaction mixture was heated to 120-125°C and stirred for 24 hours. Cooled to 50°C, added water (100 ml) stirred for 15 minutes then further cooled
to 10-15°C , pH adjusted to 5-6 with ammonium hydroxide solution. Stirred for 30
minutes at 10-15°C, filtered and cake washed with water (2x5 ml). Dried until constant
weight is reached.

Dry weight of obtained crude (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic
acid (Metyrosine) of formula-1 is 1.8 gm.
Step- (h): Purification of (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic
acid (IVIetyrosine).

The crude (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine)
obtained in step ( g) 1.8 gm) was dissolved in water (180 ml) by heating the reaction
mixture to 90°C. Darco (Charcoal) was added and stirred for 10-15 minutes at same
temperature. The resulting reaction mixture was filtered through celite bed. The filtered
reaction mass concentrated up to half volume reached under reduced pressure. Cooled
to 10°C and stirred for a period of 30 minutes at same temperature. Filtered the
resulting solid, washed with water. Dried until constant weight is reached.
Dry weight of obtained pure (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic
acid (Metyrosine) of formula-1 was 0.8 gm. The product is matching in all respects with
compounds of Metyrosine obtained from EXAMPLE-1 (Step-h).
Purity: 99.98%. Chiral purity by HPLC: 100.0%.

Advantages of the invention
1.The process does not use highly hazardous chemical like potassium and
sodium cyanide, sodium nitrite.

2. The resolution step required to get pure Metyrosine is avoided. Therefore this
process is an ideal process to be utilized on a commerClal scale.

3.The process does not use expensive reagents and hence the process is
economical.

4. There is no handling of toxic chemicals like CF3SO3H, BBra, HI and hence the
process is safe.

5). There is no step of chromatography to separate isomers and hence the
process can be used commerClally

6). Moreover the present process involves cheap raw material like protected L-
Alanine, which is commerClally available natural amino acid.

We Claim
1.Novel compound of the formula (2)


Wherein R1-R5= H, Cl, Br and F; R6= isobutyl, tert-butyl; R7= trifluoroacetyl, acetyl and benzoyl group, R8= methyl, ethyl and isopropyl group, which is useful for the preparation of Metyrosine of the formula (1)

2. Novel compound of the formula (3)
Wherein R1-R5= H, Cl, Br and F; R8= methyl, ethyl and isopropyl, which is useful for the preparation of Metyrosine of the formula-(1)

3. An improved process for the preparation of Metyrosine which is (2S)-2-Amino-3-(4-hydroxyphenyl)-2-methyl propanoic acid, of the formula (1)

with a compound of formula-(25)

Wherein R1 to R5 represent H, Cl, Br, and F,
at a temperature in the range from about -50 to 100°C for a period in the range of 13 to 15 hours and in the presence of a base and an organic solvent to provide a compound of the formula-(26)

Wherein R1 to R5 represent the same as defined above, (b). deprotecting the BOC group in the compound of formula-(26) using an acid at a temperature in the range from about -10 to 55°C and for a period in the range from 2 to 20 hours to provide a compound of the formula-(27)

wherein R1 to R5 represent the same as defined above

(c). cyclising the compound of the formula-(27) with the compound of formula-(28)

wherein R6 represents iso-butyl or tert-butyl
in an organic solvent at a temperature in the range from about 10 to 100°C and for a
period in the range from 4 to 10 hours to provide compound of the formula-(29).

wherein R1 to R5 represent the same as defined above, R6 represents isobutyl or tert-butyl.

(d). protecting the amine group of the compound of the formula-(29) with a suitable amine protecting group in the presence of a base and an organic

solvent at a temperature in the range from about -10 to 40°C and for a duration in the range from 5 to 6 hours to give a compound of the formula-(30).

wherein R1 to R6 represent the same as defined above and R7 represents an
amine protecting group like trifluoroacetyl, acetyl and benzoyl etc.

(e). reacting the compound of the formula-(30) with a compound of formula-(31)

wherein R8 represents methyl or ethyl or isopropyl group and X= Chloride, bromide, iodide in the presence of a base and an organic solvent at a temperature in the range from about -50 to 50°C and for a duration in the range from 1 to 6 hours to provide a novel compound of the formula-(2)

wherein R1 to R7 represent the same as defined above and R8 represents methyl or ethyl or isopropyl

(f). hydrolyzing the novel compound of the formula-(2) using a base followed by an acid in the presence of an organic solvent and the duration of the base hydrolysis ranging from 1 to 10 hours at a temperatures in the range from about 0 to 60°C, the duration of the acidic hydrolysis ranging from 1 to 10 hours and at a ambient temperatures in the range from about 0 to 90°C to provide the novel compound of formula-(3)

wherein R1 to R5 and R8 represent the same as defined above.

(h). hydrolyzing followed by demethylation of the compound of the formula-(3)
with an acid for a duration in the range from 1 to 30 hours and at a temperature
in the range from about 25 to 140°C, to give crude Metyrosine of the formula-

(i)purifying the crude Metyrosine of the formula-(1) formed in step-(h) using
water and organic solvents like methanoi.ethanol, toluene, hepatane,
ethylacetate, dimethyl formamide and dimethylsulphoxide and preferably
dimethylformaide and water and most preferably water to provide pure
Metyrosine of theformula-(1).

4. A process for the preparation of novel intermediate of the formula-(2) as
defined above which is useful for the preparation of Metyrosine of the formula-

(1) as defined above which comprises

(a), reacting N-BOC-L-alanine of the formula-(24)

with a compound of formula-(25)

wherein R1 to R5 represent H, CL, Br, and F,

at a temperature in the range from about -50 to 100°C for a period in the range of 13 to 15 hours and in the presence of a base and an organic solvent to provide a compound of the formula-(26)

wherein R1 to R5 represent the same as defined above,

(b). deprotecting the BOC group in the compound of formula-(26) using an acid at a temperature in the range from about -10 to 55°C and for a period in the range from 2 to 20 hours to provide a compound of the formula-(27)

wherein R1 to R5 represent the same as defined above

(c). cyclising the compound of the formula-(27) with the compound of formula-

wherein R6 represents iso-butyl or tert-butyl

in an organic solvent at a temperature in the range from about 10 to 100°C and for a period in the range from 4 to 10 hours to provide compound of the formula-(29).

wherein R1 to R5 represent the same as defined above, R6 represents isobutyl or tert-butyl.

(d). protecting the amine group of the compound of the formula-(29) with a suitable amine protecting group in the presence of a base and an organic solvent at a temperature in the range from about -10 to 40°C and for a duration in the range from 5to 6 hours to give a compound of the formula-(30)

wherein and R1 to R6 represent the same as defined above and R7 represents
an amine protecting group like trifluoroacetyl, acetyl and benzoyl etc.

(e). reacting the compound of the formula-(30) with a compound of formula-(31)

wherein R8 represents methyl or ethyl or isopropyl group and X= Chloride, bromide, iodide in the presence of a base and an organic solvent at a temperature in the range from about -50 to 50°C and for a duration in the range from 1 to 6 hours to provide a novel compound of the formula-(2)

wherein R1 to R7 represent the same as defined above and R8 represents
methyl or ethyl or isopropyl

5. A process for the preparation of novel intermediate of the formula (3) as
defined above which is useful for the preparation of Metyrosine of the formula-(1)
as defined above which comprises.

(a), reacting N-BOC-L-alanine of the formula-(24)

with a compound of formula-(25)

wherein R1 to R5 represent H, CL, Br, and F,
at a temperature in the range from about -50 to 100°C for a period in the range of 13 to 15 hours and in the presence of a base and an organic solvent to provide a compound of the formula-(26)

wherein R1 to R5 represent the same as defined above, (b). deprotecting the BOC group in the compound of formula-(26) using an acid at a temperature in the range from about -10 to 55°C and for a period in the range from 2 to 20 hours to provide a compound of the formula-(27)

wherein R1 to R5 represent the same as defined above
(c). cyclising the compound of the formula-(27) with the compound of formula-
(28)

wherein R6 represents iso-butyl or tert-butyl
in an organic solvent at a temperature in the range from about 10 to 100°C and for a
period in the range from 4 to 10 hours to provide compound of the formula-(29).

wherein R1 to R5 represent the same as defined above, R6 represents isobutyl or tert-butyl.

(d). protecting the amine group of the compound of the formula-(29) with a suitable amine protecting group in the presence of a base and an organic solvent at a temperature in the range from about -10 to 40°C and for a duration in the range from 6 to 5 hours to give a compound of the formula-(30)

wherein and R1 to R6 represent the same as defined above and R7 represents
an amine protecting group like trifluoroacetyl, acetyl and benzoyl etc.

(e). reacting the compound of the formula-(30) with a compound of formula-(31)

wherein R8 represents methyl or ethyl or isopropyl group and X= Chloride, bromide, iodide in the presence of a base and an organic solvent at a temperature in the range from about -50 to 50°C and for a duration in the range from 1 to 6 hours to provide a novel compound of the formula-(2)

wherein R1 to R7 represent the same as defined above and R8 represents methyl or ethyl or isopropyl

(f). Hydrolysing the novel compound of the formula-(2) using a base followed by an acid In the presence of an organic solvent and the duration of the base hydrolysis ranging from 1 to 10 hours at a temperatures in the range from about 0 to 60°C, the duration of the acidic hydrolysis ranging from 1 to 10 hours and at a ambient temperatures in the range from about 0 to 90°C to provide the novel compound of formula-(3)

wherein R1 to R5 and R8 represent the same as defined above.

6. A process as Claimed in Claims 3 to 8 wherein in the step-(a) N-Boc-L-Alanine
acid of the formula-(24) is reacted with compound of formula-(25) wherein
preferably R1,R2, R4,R5 represent hydrogen and R3 represents halogen, more preferably R1,R5 represent s hydrogen and R2, R3,R4 represent halogen and still more preferably R1,R3,R5 represent hydrogen and R2,R4 represent halogen in the presence of Isobutylchloroformate more preferably Ethylchloroformate and organic base to provide the compound of formula-(26)

7. A process as Claimed in Claim 6 wherein the reaction is carried out in organic solvents such as toluene, THF, dichloromethane, ethylene dichloride, chloroform more preferably dichloromethane in the presence of organic base and most preferable base is N-Methylmorpholine at a temperature preferably in the range - 35 to 5°C, the duration of the reaction preferably being in the range from 12 to 14 hours.

8. A process as Claimed in Claims 3 to 7 wherein in the step-(b) the compound of the formula-(26) is treated with acids in organic solvent to get the compound of the formula-(27) the acid used in the reaction being selected from the group consisting of hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, trifluoroacetic acid, methane sulfonicacid, benzene sulfonicacid, phosphoric acid, p-toluenesulfonic acid and preferably hydrochloric acid, the amount of acid used being in the range of 1-10 molar equivalents and preferably 7-9 molar equivalents, the solvent used being selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile , preferably methanol, the reaction temperature used preferably being in the range from 15 to 30°C and the duration of the reaction preferably being in the range from 15 to 18 hours.

9. A process as Claimed in Claims 3 to 8 wherein in the step-(c) the compound of formula-(27) is treated with a compound of formula-(28) wherein R6 represents
tert- butyl more preferably isobutyl in a organic solvent to provide compound of
formula-(29)

10.A process as Claimed in Claim 9 wherein the reaction is carried out in the
presence of organic solvents such as toluene, THF, MTBE, pentane, hexane,
heptane more preferably toluene at ambient temperatures in the range preferably
from about 45 to 55°C and the duration of the reaction preferably ranging from 6 to
8 hours.

11. A process as Claimed in Claims 3 to 10 wherein the in the step-(d) the amine group in the compound of the formula-(29) is protected with suitable amine protecting groups more preferably group being trifluoroacetyl in the presence of organic base in a organic solvent to provide compound of formula-(30)

12. A process as Claimed in Claim 11 wherein the base used is selected from the group consisting of imidazole, lutidine, pyridine, DIPEA, triethylamine and preferably triethylamine, the amount of the base used being in the range of 1-5 molar equivalents preferably 1-2 molar equivalents, the solvent used being selected from ether solvents such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, dimethylformamide, chlorinated solvents such as methylene chloride, ethylene dichloride, chloroform and preferably using dichloromethane, the reaction temperature preferably ranging from about preferably in the range from -5 to 5°C, the duration of the reaction preferably ranging from 2 to 3 hours.

13. A process as Claimed in Claims 3 to 12 wherein in the step-(e) the , compound of the formula-(30) is reacted with compound of the formula-(31) wherein R8
represents methyl,ethyl and isopropyl more preferably methyl in the presence of organic base in a organic solvent to provide the novel compound of formula-(2).

14. A process as Claimed in Claims 13 wherein the base used selected from group consisting of potassium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium hydride, LDA, potassium hydroxide, sodium hydroxide, Sodium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amlde, potassium bis(trimethylsilyl)amide preferably lithium bis(trimethylsilyl)amide, the amount of base used being in the range of 1-3 molar equivalents preferably using 1-2 molar equivalents, the solvent used being selected from ether solvents such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, dimethylformamide, hydrocarbon solvents such as toluene, xylene, hexane, cyclohexane preferably tetrahydrofuran.

15. A process as Claimed in Claim 14 wherein the reaction temperature preferably ranging from about -30 to 0°C, the duration of the reaction being preferably ranging from 2 to 3 hours.

16. A process as Claimed in Claims 14 & 15 wherein the base used is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, triton-B preferably potassium hydroxide, the acid used being selected from the group consisting of hydrochloric acid, hydrogen bromide, sulfuric acid preferably sulfuric acid.

17. A process as Claimed in Claims 15 to 16 wherein the solvent used is selected from ether solvents such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, dimethylformamide, alcoholic solvents such as methanol, ethanol, isopropyl
alcohol, tert-butyl alcohol preferably Isopropyl alcohol. The duration for basic hydrolysis preferably being in the range from 2 to 4 hours at a temperature preferably in the range from about 40-50°C, the duration for acidic hydrolysis preferably being in the range from 1 to 3 hours at a temperature in the range from about 60-75°C.

18. Novel compounds of the formula 2 & 3 useful for the preparation of
Metyrosine of the formula-(1) substantially as herein described

19. A process for the preparation of Novel compounds of the formula 2 & 3
useful for the preparation of Metyrosine of the formula-(1) substantially as herein
described

20. A process for the preparation of Metyrosine of the formula-(1) substantially as
herein described with reference to the Examples