DESC:RELATED PATENT APPLICATION(S)
This application claims the benefit of Indian Patent Application No. 201741004492 filed on February 07, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention describes a preparation of substantially pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I) or Metyrosine. The present invention is also directed to a novel method of resolving 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV), which is used as an intermediate in the preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I) or Metyrosine.

BACKGROUND OF THE INVENTION

Metyrosine is chemically known as (S)-2-amino-3-(4-hydroxyphenyl)-2-methyl propanoic acid (I) and is an antihypertensive drug used in hypertension caused mostly due to Pheochromocytoma. The ‘S’ isomer of 2-amino-3-(4-methoxyphenyl)-2-methylpropanoic acid also known as Metyrosine is responsible for exhibiting its pharmacological activity while the ‘R’ isomer is totally inactive. Hence, a commercially viable stereo selective synthesis of ‘S’ isomer i.e. Metyrosine, involving stereo-selectively pure intermediates become important.

The synthesis of Metyrosine has been reported in many patents and non-patent literature, the contents of which are hereby incorporated as reference in their entirety.

US8841486 describes the process for the preparation of certain intermediates that are diastereomerically or enantiomerically pure and can be converted to Metyrosine, but the limitations of this process lie in the use of expensive chiral reagents used to introduce the stereo center.

US2868818 covers the synthesis of Metyrosine by reacting 3-amino-2-phenylbutanoic acid with 2,2-dichloroacetyl chloride in presence of sodium hydroxide at 0oC, followed by addition of cold fuming nitric acid and hydrogenated at low pressure in presence of platinum oxide. The product so obtained was treated with sulfuric acid and sodium nitrate at reduced temperature to form a diazonium compound, concentrated and dissolved in ethanol and acid treated to obtain a free compound. Platinum oxide is a highly expensive reagent and its use at industrial scale is not viable. Also, separation of the Metyrosine isomers makes this process lengthy and tedious.

Similarly, in US3399226 the process employs Raney Ni and platinum oxide as catalyst which are too expensive and hence not suitable for commercial use.

Also, few non-patent literature references have described the synthesis and purification processes for the preparation of Metyrosine, but their commercial scale implementation is limited due to low yield, use of platinum oxide, expensive metals like Raney Ni, palladium, platinum and formation of hazardous azide intermediates.

The present inventors therefore report a novel synthetic and purification process where the diastereomers of Metyrosine are easily separable using crystallization and the process is cost effective, simple and employs less expensive chemicals which makes it more feasible at an industrial scale.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a novel process with high stereo selection for the preparation of substantially pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I).

Yet another object of the invention is to provide the use of L- (+)-tartaric acid for the resolution of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV).

In one aspect of the invention, there is provided a process for preparing (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I),

(I)

the said process comprising the steps of:

a) converting1-(4-methoxyphenyl) propan-2-one (V) to 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) by treatment with sodium cyanide and ammonium chloride;

b) treating 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) obtained in step a) with L-(+)-tartaric acid to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III),

c) converting L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III) obtained in step b) to free base (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) in presence of base; and

d) hydrolyzing (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in step c) by treatment with aqueous hydro bromide solution and purifying to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) with more than 99.9% chiral purity (vide chiral HPLC).

In some embodiment of the invention, the base used in step c) of the above described process for preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I) is selected from alkalis comprising potassium hydroxide, lithium hydroxide, sodium hydroxide or the like; bicarbonates selected from potassium bicarbonate, lithium bicarbonate or sodium bicarbonate or the like.

In another aspect of the invention, there is provided a process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I), comprising:
a. Suspending crude Metyrosine in a suitable polar protic solvent,
b. adjusting pH to 12-13.0 by using suitable base,
c. treating with neutral charcoal and passing through 0.2-micron filter,
d. adjusting pH to 9.0 to 10.0 using concentrated hydrochloric acid,
e. isolating pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) with purity greater than 99.0%.

In some embodiment of the invention, the polar protic solvent used in the above described process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) is water.

In some other embodiment of the invention, the base used in the above described process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) is sodium hydroxide.

In some embodiment of the invention, there is provided a process for the preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crystalline form. In some other embodiment of the invention, there is provided a process for the preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crystalline form characterized by X-ray powder diffraction (XRPD) pattern as shown in figure 1 and is having peaks at 2 theta values with (+ 0.2) at 9.15 ,10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36,27.81,30.07,31.53,33.72 and 36.79.

In some embodiment of the invention, there is provided a process for the preparation of crystalline form of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I), characterized by X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values with (+ 0.2) at 9.15 ,10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36, 27.81, 30.07, 31.53, 33.72 and 36.79, the said process comprising the steps of:
a) converting 1-(4-methoxyphenyl) propan-2-one (V) to 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) by treatment with sodium cyanide and ammonium chloride;
b) treating 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) obtained in step a) with L-(+)-tartaric acid to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III),
c) converting L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III) obtained in step b) to free base (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) in presence of base;
d) hydrolyzing (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in step c) by treatment with aqueous hydro bromide solution to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crude form;
e) suspending crude (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine obtained in step d) in a suitable polar protic solvent;
f) adjusting the pH of the suspension obtained in step e) to 12.0 to13.0 by using suitable base;
g) treating with neutral charcoal and passing through 0.2-micron filter;
h) adjusting pH of the filterate obtained in step g) to 9.0 to 10.0 using concentrated hydrochloric acid; and
i) isolating crystalline form of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I).

In another aspect of the invention, there is provided a compound (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) having a purity of at least 99.0% by HPLC and chiral purity greater than 99.9%.

The object of the current invention is to develop an unique method for synthesis of stereo selective Metyrosine having more than 99.9% chiral purity which comprises:
a) addition of methanol, aqueous ammonia, sodium cyanide and ammonium chloride to 1-(4-methoxyphenyl)propan-2-one (V) to isolate 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) with greater than 95% yield and with more than 97% purity by HPLC;
b) treatment of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) with L-(+)-tartaric acid in methanol at 10–15°C to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III);
c) The 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile salt with L-(+)-tartaric acid (III) is neutralized with aqueous sodium bicarbonate or any other suitable base to isolate (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) with more than 90% purity; and
d) (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in the above stage is hydrolyzed with aqueous hydro bromide solution under suitable reaction conditions followed by purification to remove undesired isomer and impurities by isolating at an optimum pH of 9.0 to 10; preferably at pH 9.0 to 9.5. to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I). Metyrosine (I) thus obtained is having more than 99.9% chiral purity (vide chiral HPLC).

2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) was treated with L-(+)-tartaric acid in methanol under suitable reaction conditions to isolate the corresponding 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile salt with L- (+)-tartaric acid (III).

The closest prior art JPS63255255 (A) which deals with the resolution of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile involves its treatment with acetyl phenyl glycine to form the corresponding salt which is then neutralized and followed by reaction work up of extraction and isolation of an oily compound, which on further work up yields a solid isomer of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile. This is further treated with either D-tartaric acid or L-tartaric acid to isolate finally the required optical isomer of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile salt with tartaric acid.
In the subsequent reaction stages, the separated optical isomer of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile salt with tartaric acid (III) is converted to (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I).

This process employs repeated acid – base formation and neutralization sequence thereby reducing the final yield drastically. The reaction workups are tedious and industrially highly unsuitable.

The present inventors have therefore come up with a novel process for the preparation of substantially pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the Fourier-transform infrared (FT-IR) spectrum ofMetyrosine (I)
Figure 2 illustrates the Proton nuclear magnetic resonance (1H-NMR) spectrum of Metyrosine (I)
Figure 3 illustrates the High-performance liquid chromatography (HPLC) chromatogram of Metyrosine (I)
Figure 4 illustrates the Chiral High-performance liquid chromatography (chiral HPLC) chromatogram of Metyrosine (I)
Figure 5 illustrates the specific optical rotation (SOR) of Metyrosine (I)
Figure 6 illustrates X-Ray powder diffraction (XPRD) pattern of Metyrosine (I)

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process with high stereo selection for the preparation of substantially pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I).

In one aspect of the invention, there is provided a process for preparing (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I),

(I)

the said process comprising the steps of:

a) converting1-(4-methoxyphenyl) propan-2-one (V) to 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) by treatment with sodium cyanide and ammonium chloride;

b) treating 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) obtained in step a) with L-(+)-tartaric acid to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III),

c) converting L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III) obtained in step b) to free base (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) in presence of base; and

d) hydrolyzing (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in step c) by treatment with aqueous hydro bromide solution and purifying to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) with more than 99.9% chiral purity (vide chiral HPLC).

SCHEME 1

The process of the present invention is described in Scheme 1. The first step comprises addition of equimolar quantities ofsodium cyanide and ammonium chlorideto 1-(4-methoxyphenyl)propan-2-one (V) at a temperature of 25 -30°C and the reaction temperature is brought down to 5-10°C. Molar ratio of sodium cyanide/ammonium chloride to 4-methoxy phenyl acetone is maintained at about 2:1. Bringing down the reaction temperature to 5-10°C and maintaining the mole ratio is crucial for obtaining a highly pure product 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV).

The second step involves resolving 2-amino-3-(4-methoxyphenyl)-2-methyl propanenitrile (IV) with L-(+)-tartaric acid in a suitable solvent via the formation of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrilesalt with L-(+)-Tartaric acid (III). Temperature of the reaction should be maintained between 10–15°C to avoid decomposition of the product, which results in lesser purity and lower yield of the product. The suitable solvent employed for this reaction step is selected from the group of alcohols comprising methanol, ethanol, isopropanol, n-propanol, n-butanol or the like; water or mixtures thereof.

Optionally, the obtained solid is further purified by adding 25% methanol and water followed by stirring for 2-3 hours at 10-15°C, then filtered and washed the solid with 25% DM water in Methanol (10-15°C).

The third step, which forms another part of the embodiment describes the formation of (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) from 2-amino-3-(4-methoxy phenyl)-2-methylpropanenitrile salt with L- (+)-Tartaric acid (III) by adjusting the pH to 7.0 to 7.5 with suitable base, at a temperature of 5-10°C. Criticality of this step lies in maintaining the pH of the reaction at 7.0-7.5; pH above 7.5 would decompose the product and at pH below 7.0 the yields and purity of the product are low.

In one aspect, the base used in the third step for adjusting pH could be selected from alkalis comprising potassium hydroxide, lithium hydroxide, sodium hydroxide or the like; bicarbonates selected from potassium bicarbonate, lithium bicarbonate or sodium bicarbonate or the like; preferably the base employed is aqueous sodium bicarbonate solution, most preferably it is 7-8% aqueous sodium bicarbonate solution.

The final step which forms part of the embodiment, involves the conversion of (S)-2-amino-3-(4-methoxyphenyl)-2-methyl propanenitrile (II) to (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) by treating with aqueous hydro bromide solution (47%) at 90-95°C for 12-14 hours.

Metyrosine thus obtained is purified by isolating the solid at optimum pH 9.0 to 9.5 and the obtained solid was optionally taken in water and the pH is further adjusted to12 to 13 by using 30% aqueous sodium hydroxide solution. Again the pH of the filtrate is adjusted to 9.0 to 9.5 to isolate the substantially pure Metyrosine having a chiral purity by HPLC of about 99.95%.

In another aspect of the invention, there is provided a process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I), comprising:
a. Suspending crude Metyrosine in a suitable polar protic solvent,
b. adjusting pH to 12-13.0 by using suitable base,
c. treating with neutral charcoal and passing through 0.2-micron filter,
d. adjusting pH to 9.0 to 10.0 using concentrated hydrochloric acid,
e. isolating pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) with purity greater than 99.0%.

In some embodiment of the invention, the polar protic solvent used in the above described process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) is water.

In some other embodiment of the invention, the base used in the above described process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) is sodium hydroxide.

In one aspect the pH of the reaction mass in the final step is adjusted to 9.0 to 10, preferably at 9.0 to 9.5 by using 30% aqueous sodium hydroxide solution, which is very critical to control undesired isomer and impurities within the specified limit in the final product.

Metyrosine (I) obtained by the process of the present invention is having undesired isomer (R)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid less than 0.05 % by chiral HPLC, preferably less than 0.03 %.

Undesired Isomer

Metyrosine (I) obtained by the process of the present invention is analyzed by FT-IR, 1HNMR and XRD, wherein the characteristic X-Ray powder diffraction is as shown in figure 6, wherein the X-ray diffraction peaks of Metyrosine obtained by the process of the invention may have 2(?) values (+ 0.2) at 9.15, 10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36, 27.81, 30.07, 31.53, 33.72 and 36.79.

In some embodiment of the invention, there is provided a process for the preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crystalline form. In some other embodiment of the invention, there is provided a process for the preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crystalline form characterized by X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values with (+ 0.2) at 9.15 ,10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36,27.81,30.07,31.53,33.72 and 36.79.

In some embodiment of the invention, there is provided a process for the preparation of crystalline form of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I), characterized by X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values with (+ 0.2) at 9.15 ,10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36, 27.81, 30.07, 31.53, 33.72 and 36.79, the said process comprising the steps of:
a) converting 1-(4-methoxyphenyl) propan-2-one (V) to 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) by treatment with sodium cyanide and ammonium chloride;
b) treating 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) obtained in step a) with L-(+)-tartaric acid to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III),
c) converting L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III) obtained in step b) to free base (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) in presence of base;
d) hydrolyzing (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in step c) by treatment with aqueous hydro bromide solution to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crude form;
e) suspending crude (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine obtained in step d) in a suitable polar protic solvent;
f) adjusting the pH of the suspension obtained in step e) to 12.0 to13.0 by using suitable base;
g) treating with neutral charcoal and passing through 0.2-micron filter;
h) adjusting pH of the filterate obtained in step g) to 9.0 to 10.0 using concentrated hydrochloric acid; and
i) isolating crystalline form of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I).

In another aspect of the invention, there is provided a compound (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) having a purity of at least 99.0% by HPLC and chiral purity greater than 99.9%.

In another embodiment, the stereo selectivity of Metyrosine obtained by the present process is analyzed by specific optical rotation (SOR) which is within the limit of +185 to +195, as per the USP Monograph.

The following examples further illustrate the present invention, but should not be construed inanyway, as to limit its scope.

EXAMPLES
EXAMPLE-1:

Preparation of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV):
100 g (0.609 mol) of 1-(4-methoxyphenyl) propan-2-one (V) was dissolved in 300 mL of methanol in a clean and dry round bottom flask followed by addition of 150 mL aqueous ammonia and 59.6 g (1.22 mol) of sodium cyanide at a temperature of 25-30°C, then cooled to 5-10°C. To the above mixture 64.8 g (1.22 mol) of ammonium chloride (solution in 200 mL of DM water) was added slowly at 0-10°C for 30 minutes. The reaction mass was maintained for 12 hours at 25-30°C. The reaction was monitored by HPLC, upon complying, the reaction mixture was quenched with 20% aqueous ferrous sulphate heptahydrate solution. The compound so obtained was extracted with dichloromethaneand washed the dichloromethane layer with water and aqueous sodium chloride solution.
The resulting organic layer was evaporated below 30°C under vacuum to give 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) with 97% purity by HPLC, yield of 95-99%, moisture content not more than 1.0%.

EXAMPLE-2:

Preparation of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile salt with L- (+)-Tartaric acid (III):
300 mL of methanol was taken in a clean and dry round bottom flask and cooled to 10-15°C, and 100 g (0.53 mol) of 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) was added. To the above solution 87 g (0.578 mol) of L-(+)-tartaric acid solution in 1000 mL of methanol was added over a period of 25-30 minutes and maintained the temperature for 2-3 hours at 10-15°C. The solid so obtained was filtered and washed with chilled 25% DM water in methanol and dried to get L- (+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate (III). The solid obtained in above step was dissolved in 2500 mL of 25% DM Water in methanol and stirred for 2-3 hours at 10-15oC, filtered and washed with 100 mL of chilled 25% DM Water in methanol (10-15°C). The solid so obtained was directly used in the next step.
EXAMPLE-3:

Preparation of (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II):
To the solid L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate (III) obtained in above step was added 150 mL of DM water and the pH was adjusted to 7.0-7.5 by adding ~ 7-8 % aqueous sodium bicarbonate solution at 5-10°C. The above mixture was stirred for 10-15 minutes and 200 mL of dichloromethane was added and stirred. The aqueous and organic layers were separated and the aqueous layer was treated with dichloromethane at 5-10°C. The organic layer was washed with DM Water and 10% aqueous sodium chloride. The organic layer was dried over sodium sulphate and evaporated under vacuum below 30°C. The crude product was degassed for 1-2 hours to give 90.0% pure (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) with 10-12% yield.

EXAMPLE-4:

Preparation of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I):
100g (0.525 mol) of (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) was charged into a round bottom flask along with 500 mL of 47 % aqueous hydro bromide solution at 25-30°C. The reaction mass was maintained for 12-14 hours at 90-95°C. The reaction mass was cooled to 25-30°C, treated with neutral charcoal (NORIT CN1) and filtered through Hyflo. The filtrate was taken in a clean and dry round bottom flask, which is charged with 1400 mL of DM Water at 25-30°C and cooled to 15-20°C. The pH of the solution is maintained at 9.0-9.5 by using 30% aqueous sodium hydroxide solution. The reaction mass was maintained for 2-3 hours at 15-20°C, filtered and the solid was washed with 100 mL DM water and 250 mL methanol and dried.

To the above wet reaction mass 1400 mL of DM water was added, and pH adjusted to 12.5-13.0 by using 30% aqueous sodium hydroxide solution. The obtained solution was treated with Neutral charcoal (NORIT CN1) at 25-30oC for 15 minutes and then filtered through Hyflo. The filtrate was passed through 0.2 mm micron filter and adjusted pH to 9.0-9.5 by using concentrated hydrochloric acid at 20-25°C. The solid so obtained was filtered under vacuum and washed with DM water and methanol to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) which was found to be pure with a yield of 45-50%.

Purity by HPLC: 99.9%
Chiral purity: 99.98%
Undesired Isomer by Chiral HPLC: Less than 0.05%
LOD: NMT 1.0%
,CLAIMS:
1. A process for preparing (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I),

(I)

the said process comprising the steps of:
a) converting 1-(4-methoxyphenyl) propan-2-one (V) to 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) by treatment with sodium cyanide and ammonium chloride;
b) treating 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) obtained in step a) with L-(+)-tartaric acid to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III),
c) converting L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III) obtained in step b) to free base (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) in presence of base; and
d) hydrolyzing (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in step c) by treatment with aqueous hydro bromide solution and purifying to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) with more than 99.9% chiral purity (vide chiral HPLC).

2. The process as claimed in claim 1, wherein the base used in step c) is selected from alkalis comprising potassium hydroxide, lithium hydroxide, sodium hydroxide or the like; bicarbonates selected from potassium bicarbonate, lithium bicarbonate or sodium bicarbonate or the like

3. A process for purification of a (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I), comprising:
a. suspending crude Metyrosine in a suitable polar protic solvent,
b. adjusting pH to 12.0 to 13.0 by using suitable base,
c. treating with neutral charcoal and passing through 0.2-micron filter,
d. adjusting pH to 9.0 to 10.0 using concentrated hydrochloric acid,
e. isolating pure (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) with purity greater than 99.0%.

4. The process as claimed in Claim 3, wherein the polar protic solvent used is water.

5. The process as claimed in Claim 3, wherein the base used in is sodium hydroxide.

6. A compound (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) having a purity of at least 99.0% by HPLC and chiral purity greater than 99.9%.

7. The process as claimed in claim 1 or 3, wherein the (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) obtained is a crystalline compound characterized by X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values with (+ 0.2) at 9.15, 10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36, 27.81, 30.07, 31.53, 33.72 and 36.79.

8. A process for the preparation of crystalline form of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (I), characterized by X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values with (+ 0.2) at 9.15 ,10.00, 10.98, 12.19, 13.44, 14.89, 16.32, 18.07, 19.19, 20.12, 21.20, 22.72, 23.78, 24.48, 27.36, 27.81, 30.07, 31.53, 33.72 and 36.79

(I)

the said process comprising the steps of:
a) converting 1-(4-methoxyphenyl) propan-2-one (V) to 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) by treatment with sodium cyanide and ammonium chloride;
b) treating 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (IV) obtained in step a) with L-(+)-tartaric acid to yield L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III),
c) converting L-(+)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile tartrate salt (III) obtained in step b) to free base (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) in presence of base;
d) hydrolyzing (S)-2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile (II) obtained in step c) by treatment with aqueous hydro bromide solution to obtain (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I) in crude form;
e) suspending crude (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine obtained in step d) in a suitable polar protic solvent;
f) adjusting the pH of the suspension obtained in step e) to 12.0 to13.0 by using suitable base;
g) treating with neutral charcoal and passing through 0.2-micron filter;
h) adjusting pH of the filterate obtained in step g) to 9.0 to 10.0 using concentrated hydrochloric acid; and
i) isolating crystalline form of (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid or Metyrosine (I).